Tricyclic fused heterocycle compounds, process for preparing the same and use thereof

ABSTRACT

Compounds represented by formula (1),                    
     wherein 
     X is, for example, CH, CH 2 , CHR (wherein R is a lower alkyl group or a substituted lower alkyl group) or CRR′ (wherein R and R′ are the same as the above defined R); 
     Y is, for example, CH, CH 2  or C═O; 
     Z is, for example, O, S, S═O or SO 2 ; 
     U is C or N; 
     R 1  to R 4  are each independently, for example, a hydrogen atom, OR, SR (wherein R is the same as defined above), or an aromatic ring, a substituted aromatic ring or a heterocycle; 
     at least one of R 5  and R 8  is, for example, OH and the remaining of R 5  and R 8  are each independently, for example, a hydrogen atom or OH, optical isomers thereof, conjugates thereof or pharmaceutically acceptable salts thereof are provided. These compounds are characterized in having a wide range of pharmacological actions such as an excellent relaxing action of tracheal smooth muscles, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway and, in addition, high safety.

CLAIM OF PRIORITY

This application is a divisional of U.S. patent application Ser. No.09/980,581 filed on Feb. 26, 2002, now U.S. Pat. No. 6,602,898, which isa U.S. National Phase Application of International Application No.PCT/JP00/03592 filed on Jun. 2, 2000, which is a PCT filing of JapaneseApplication No. 11/157181 filed on Jun. 3, 1999, each of which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to novel tricyclic condensed heterocycliccompounds, their preparation method and uses. The tricyclic condensedheterocyclic compounds of the present invention have a wide range ofpharmacological actions such as the relaxing action of tracheal smoothmuscles, the inhibition of airway hypersensitivity and the inhibition ofinfiltration of inflammatory cells into the airway and are useful asdrugs such as antiasthmatic drugs.

BACKGROUND ART

Heretofore, various cyclic compounds have been proposed as the compoundsuseful for asthma and the like. For example, xanthine derivatives suchas theophylline and β₂-agonists such as salbutamol, steroids,antiallergic drugs and the like are known.

Further, various tricyclic condensed heterocyclic compounds areproposed.

Examples of such prior arts are mentioned below.

Yakugaku Zasshi, 87,(2), 198-201 (1967) discloses threedihydrodibenz[b,f]oxepin derivatives as the synthetic intermediates of anatural product but no pharmacological action and the like relating tothese compounds are described.

U.S. Pat. No. 4,104,280 describes that tricyclc condensed heterocycliccompounds containing an oxygen atom or a sulfur atom as the heterocylicatom and a substituent of —CHRCOOH or —CHRCOOCH₃ (wherein R is ahydrogen atom or a methyl group) on the benzene ring are useful asanti-inflammatory drugs and relaxants.

European Patent Publication No. 0 011 067 A1 suggests that triclycliccondensed heterocyclic compounds containing a sulfur atom as theheterocyclic atom and —(CH₂)_(n) 13 A (wherein n is 0 to 4; and A is aheterocyclic residue) as one substituent on the benzene ring areeffective for asthma, allergy and the like.

British Patent No. 2,016,466 describes that triclyclic condensedheterocyclic compounds containing an oxygen atom or a sulfur atom as theheterocyclic atom and —CH₂COR (wherein R is OH, NH₂, a C₁₋₅ alkyl groupor the like) as one substituent on the benzene ring are useful asanti-inflammatory drugs.

German Patent No. 32 03065 discloses that certain types of triclycliccondensed heterocyclic compounds containing an oxygen atom or a sulfuratom as the heterocyclic atom and various substituents on the benzenering have pharmacological actions such as analgesia, sedation,antidepression, antispastic action.

European Patent Publication No. 0 003 893 discloses that triclycliccondensed heterocyclic compounds containing oxygen or sulfur as theheterocyclic atom and having —CHR₂COOR₃ (wherein R₂ is a hydrogen atomor a methyl group; and R₃ is a hydrogen atom or —CH₂CH₂OCH₂CH₂OH) as onesubstituent on the benzene ring have pharmacological actions such asanti-inflammation, analgesia and pyretolysis.

German Patent No. 1,302,590 describes tricyclic condensed heterocycliccompounds containing sulfur as the hetero atom and having varioussubstituents on the benzene ring.

U.S. Pat. No. 4,104,280 teaches that 3-hydroxymethyl-benzo[b,f]thiepincontaining a sulfur atom as the heterocyclic atom and its derivativesare used in the treatment of allergic diseases such as allergic asthma.

Br. J. Pharmac., 82, 389-395 (1984) describes2-hydroxy-methyl-dibenzo[b,f]thiepin-5,5-dioxide which is an antagonistof prostanoids contractile for lung smooth muscles.

Japanese Pharm. Soc. Bull., 94, 299-307 (1989) suggests that2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid possiblybecomes a clinically useful substance as an anti-inflammatory, analgesicand antipyretic drug since it only has a slight effect on circulatoryorgans and the autonomic nervous system when a considerably large amountis used.

WO Publication 96/10021 describes antioxidative tricylic condensedheterocyclic compounds containing oxygen or sulfur as the heterocyclicatom and having various substitutents on the benzene ring.

WO Publication 96/25927 describes glutamic receptor blockers andcerebral function improving drugs containing oxygen or sulfur as theheterocyclic atom and having various substitutents on the benzene ring.

WO Publication 97/25985 describes tracheal smooth muscle relaxantshaving compounds containing oxygen or sulfur as the heterocyclic atomand having various substituents on the benzene ring as the effectivecomponent.

J. Org. Chem., 61,5818-5822 (1996) and Collection Czechoslov. Chem.Commum., 43, 309 (1978) describe the synthesis of dibenzoxepins anddibenzothiepins.

Terahedron, 40, 4245-4252 (1984) and Phytochemistry, 31, (3) 1068-1070(1992) describe dibenzoxepin derivatives derived from a naturalsubstance.

Chem. Pharm. Bull., 23, (10) 2223-2231 (1975) and Chem. Pharm. Bull.,26, (10) 3058-3070 (1978) describe the synthetic methods ofdibenzothiepin derivatives and the antiemetic action of these compounds.

J. Chem. Soc. Perkin Trans. 1, 3291-3294 (1991) and J. Med. Chem., 26,1131-1137 (1983) describe the synthetic methods of dibenzoxepin anddibenzothiepin derivatives and the anti-estrogenic action of thesecompounds.

As stated above, heretofore, various tricyclic condensed heterocycliccompounds have been disclosed, but they cannot be said to be sufficientin respect of therapeutic effect, prolonged action, safety (in terms ofpreventing side effects) when used as therapeutic drugs for airwaydisorders such as bronchial asthma, acute or chronic bronchitis,pulmonary emphysema and upper esophagitis and the like and lungdiseases, allergic diseases, chronic inflammation and the like. Thus,the development of novel compounds having a broad range ofpharmacological actions including an airway smooth muscle relaxingaction, an inhibition of airway hypersensitivity and an inhibition ofinfiltration of inflammatory cells into the airway and, at the sametime, high safety (reduced side effects) is demanded.

DISCLOSURE OF THE INVENTION

In view of the above described present situations, the object of thepresent invention is to provide novel compounds which have a wide rangeof pharmacological actions such as a clinically useful relaxing actionof tracheal smooth muscles, an inhibition of airway hypersensitivity andan inhibition of infiltration of inflammatory cells into the airway.

The present inventors have found as a result of strenuous investigationsof tricyclic condensed heterocyclic compounds that certain types oftricyclic condensed heterocyclic compounds having an OH group, or an OHgroup and an OR group (wherein R is a hydrogen atom or a lower alkylgroup) as the substitutent have a wide range of pharmacological actionssuch as a relaxation of tracheal smooth muscles, an inhibition of airwayhypersensitivity and an inhibition of infiltration of inflammatory cellsinto the airway and, in addition, an excellent prolonged action andsafety, and have completed the present invention on the basis of thisknowledge. Specifically, the present invention relates to the compounds,their preparation method, uses and intermediates described in thefollowing (1) to (25).

(1) A compound represented by formula (1),

wherein

when the X—Y bond is a single bond, X and Y, which may be the same ordifferent, are each independently any one selected from the groupconsisting of CW₁W₂ (wherein W₁ and W₂, which may be the same ordifferent, are each independently any one of a hydrogen atom, a halogen,a hydroxyl group, a lower alkyl group, a substituted lower alkyl group,a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C═O,and C═NOW₃ (wherein W₃ is a hydrogen atom or a lower alkyl group);

when the X—Y bond is a double bond, X and Y, which may be the same ordifferent, are each independently CW₄ (wherein W₄ is any one of ahydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, asubstituted lower alkyl group, a lower alkoxy group and an acyloxygroup);

Z is any one selected from O, S, S═O and SO₂;

U is C or N;

R₁ to R₄, which may be the same or different, are each independently anyone selected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a cycloalkyl group, asubstituted cycloalkyl group, a lower alkenyl group, a substituted loweralkenyl group, a lower alkynyl group, a substituted lower alkynyl group,a halogen, a lower alkylcarbonyl group, a substituted loweralkylcarbonyl group, a trihalomethyl group, V₁W₅ (wherein V₁ is any oneof O, S, S═O and SO₂; and W₅ is any one of a hydrogen atom, a loweralkyl group, a substituted lower alkyl group, a lower alkylcarbonylgroup and a substituted lower alkylcarbonyl group, an acyloxy group anda trihalomethyl group), a nitro group, an amino group, a substitutedamino group, a cyano group, an acyl group, an acylamino group, asubstituted acyl group, a substituted acylamino group, an aromatic ring,a substituted aromatic ring, a heterocycle and a substituted heterocycle(when U is N, R₄ does not exist in some cases);

R₅ to R₈, which may be the same or different, are each independently anyone selected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a lower alkenyl group, asubstituted lower alkenyl group, a lower alkynyl group, a substitutedlower alkynyl group, a halogen, a lower alkylcarbonyl group, asubstituted lower alkylcarbonyl group, a trihalomethyl group, V₂W₇(wherein V₂ is any one selected from O, S, S═O and SO₂; and W₇ is anyone selected from a hydrogen atom, a lower alkyl group, a substitutedlower alkyl group, a lower alkylcarbonyl group, a substituted loweralkylcarbonyl group and a trihalomethyl group), a nitro group, an aminogroup, a substituted amino group, an acylamino group, an aromatic ring,a substituted aromatic ring, a heterocycle and a substitutedheterocycle;

provided that at least one of R₅ to R₈ is a hydroxyl group [providedthat at least one of R₅, R₇ or R₈ is a hydroxy group when the X—Y bondis CH(C₂H₅)CO and R₆ is a hydroxyl group] when X is CHW₀, CW₀W, or CW₀(wherein W₀ is any one selected from a lower alkyl group and asubstituted lower alkyl group) and at least one of R₅ to R₈ is ahydroxyl group and, at the same time, at least one of the other R₅ to R₈is a group of OR (wherein R is any one selected from the groupconsisting of a hydrogen atom, a lower alkyl group, a substituted loweralkyl group, a lower alkylcarbonyl group and a substituted loweralkylsilyl group) when X is other than CHW₀, CW₀W₀ or CW₀ (wherein W₀ isany one selected from a lower alkyl group and a substituted lower alkylgroup);

in addition, when the X—Y is CH₂CH₂, CHBrCH₂, CH₂CO, CHBrCO, CH═CH,CH═COCOCH₃ or CH═COCH₃,

at least one of R₁ to R₄ is an aromatic ring, a substituted aromaticring, a heterocycle or a substituted heterocycle (provided that whenboth R₆ and R₇ are hydroxyl groups, any one of R₁ to R₄ is not a phenylgroup); or

at least one of R₁ to R₄ is SW₈ (wherein W₈ is a lower alkyl group or asubstituted lower alkyl group) or S(O)W₉ (wherein W₉ is a lower alkylgroup or a substituted lower alkyl group) (provided that R₇ is ahydrogen atom when Z is O); or

R₂ is either a lower alkyl group or a substituted lower alkyl group and,at the same time, R₈ is a hydroxyl group (provided that the number ofcarbon atoms of the lower alkyl group is 3 or more when Z is O); or

at least one of R₁ to R₄ is a lower alkylcarbonyl group (provided thatthe number of carbon atoms of the lower alkyl group is 3 or more), acycloalkylcarbonyl group or a cycloalkenylcarbonyl group and, at thesame time, R₈ is a hydroxyl group; or

at least one of R₁ to R₄ is a cyano group; or

at least one of R₁ to R₄ is a halogen and, at the same time, Z is anyone of S, S═O and SO₂; or

R₅ and R₆ are hydroxyl groups and, at the same time, Z is S; or

at least one of R₁ to R₄ is —C(═NOR)CH₃ (wherein R is a hydrogen atom ora lower alkyl group), an optical isomer thereof, a conjugate thereof ora pharmaceutically acceptable salt thereof.

(2) The compound stated in the above (1), wherein R₆ is a hydroxylgroup.

(3) The compound stated in the above (1), wherein R₆ and R₇ are hydroxylgroups.

(4) The compound stated in the above (1), wherein R₆ and R₈ are hydroxylgroups.

(5) The compound stated in the above (1), wherein R₅ and R₆ are hydroxylgroups.

(6) The compound stated in any one of the above (1) to (5), wherein theX—Y bond is a single bond and X is CW₁W₂ (wherein at least one of W₁ andW₂ is any one selected from a lower alkyl group, a substituted loweralkyl group, a cycloalkyl group and a cycloalkenyl group) or the X—Ybond is a double bond and X is CW₃ (wherein W₃ is any one selected alower alkyl group, a substituted lower alkyl group, a cycloalkyl groupand a cycloalkenyl group).

(7) The compound stated in any one of the above (1) to (6), wherein Y isCO.

(8) The compound stated in the above (6), wherein the lower alkyl groupis any one of a methyl group, an ethyl group, a n-propyl group, anisopropyl group, n-butyl group, a sec-butyl group, an isobutyl group anda tert-butyl group.

(9) The compound stated in any one of the above (1) to (5), wherein R₂or R₃ is any one of a heterocycle, a substituted heterocycle, anaromatic ring and a substituted aromatic ring.

(10) The compound according to any one of the above (1) to (5), whereinthe heterocyle is an aromatic heterocyle.

(11) The compound according to any one of the above (1) to (5), whereinR₂ or R₃ is SW₈ (wherein W₈ is a lower alkyl group or a substitutedlower alkyl group) or S(O)W₉ (wherein W₉ is a lower alkyl group or asubstituted alkyl group).

(12) The compound stated in the above (11), wherein the lower alkylgroup is any one of a methyl group, an ethyl group, a n-propyl group, anisopropyl group, an n-butyl group, a sec-butyl group, an isobutyl groupand a tert-butyl group.

(13) The compound stated in any one of the above (1) to (12), wherein Zis S.

(14) The compound stated in the above (1) which is7,8-dihydroxy-11-ethyl-10,11-dihydrodibenzo[b,f]thiepin-10-one.

(15) The compound stated in the above (1) which is11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one.

(16) The compound stated in the above (1) which is7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-one.

(17) A method of preparing a compound represented by formula (1),

wherein

when the X—Y bond is a single bond, X and Y, which may be the same ordifferent, are each independently any one selected from the groupconsisting of CW₁W₂ (wherein W₁ and W₂, which may be the same ordifferent, are each independently any one of a hydrogen atom, a halogen,a hydroxyl group, a lower alkyl group, a substituted lower alkyl group,a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C═O,and C═NOW₃ (wherein W₃ is a hydrogen atom or a lower alkyl group);

when the X—Y bond is a double bond, X and Y, which may be the same ordifferent, are each independently CW₄ (wherein W₄ is any one of ahydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, asubstituted lower alkyl group, a lower alkoxy group and an acyloxygroup);

Z is any one selected from O, S, S═O and SO₂;

U is C or N;

R₁ to R₄, which may be the same or different, are each independently anyone selected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a cycloalkyl group, asubstituted cycloalkyl group, a lower alkenyl group, a substituted loweralkenyl group, a lower alkynyl group, a substituted lower alkynyl group,a halogen, a lower alkylcarbonyl group, a substituted loweralkylcarbonyl group, a trihalomethyl group, V₁W₅ (wherein V₁ is any oneof O, S, S═O and SO₂; and W₅ is any one of a hydrogen atom, a loweralkyl group, a substituted lower alkyl group, a lower alkylcarbonylgroup and a substituted lower alkylcarbonyl group, an acyloxy group anda trihalomethyl group), a nitro group, an amino group, a substitutedamino group, a cyano group, an acyl group, an acylamino group, asubstituted acyl group, a substituted acylamino group, an aromatic ring,a substituted aromatic ring, a heterocycle and a substituted heterocycle(when U is N, R₄ does not exist in some cases);

R₅ to R₈, which may be the same or different, are each independently anyone selected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a lower alkenyl group, asubstituted lower alkenyl group, a lower alkynyl group, a substitutedlower alkynyl group, a halogen, a lower alkylcarbonyl group, asubstituted lower alkylcarbonyl group, a trihalomethyl group, V₂W₇(wherein V₂ is any one selected from O, S, S═O and SO₂; and W₇ is anyone selected from a hydrogen atom, a lower alkyl group, a substitutedlower alkyl group, a lower alkylcarbonyl group, a substituted loweralkylcarbonyl group and a trihalomethyl group), a nitro group, an aminogroup, a substituted amino group, an acylamino group, an aromatic ring,a substituted aromatic ring, a heterocycle and a substitutedheterocycle;

provided that at least one of R₅ to R₈ is a hydroxyl group [providedthat at least one of R₅, R₇ or R₈ is a hydroxy group when the X—Y bondis CH(C₂H₅)CO and R₆ is a hydroxyl group] when X is CHW₀, CW₀W₀ or CW₀(wherein W₀ is any one selected from a lower alkyl group and asubstituted lower alkyl group) and at least one of R₅ to R₈ is ahydroxyl group and, at the same time, at least one of the other R₅ to R₈is a group of OR (wherein R is any one selected from the groupconsisting of a hydrogen atom, a lower alkyl group, a substituted loweralkyl group, a lower alkylcarbonyl group and a substituted loweralkylsilyl group) when X is other than CHW₀, CW₀W₀ or CW₀ (wherein W₀ isany one selected from a lower alkyl group and a substituted lower alkylgroup);

in addition, when the X—Y is CH₂CH₂, CHBrCH₂, CH₂CO, CHBrCO, CH═CH,CH═COCOCH₃ or CH═COCH₃,

at least one of R₁ to R₄ is an aromatic ring, a substituted aromaticring, a heterocycle or a substituted heterocycle (provided that whenboth R₆ and R₇ are hydroxyl groups, any one of R₁ to R₄ is not a phenylgroup); or

at least one of R₁ to R₄ is SW₈ (wherein W₈ is a lower alkyl group or asubstituted lower alkyl group) or S(O)W₉ (wherein W₉ is a lower alkylgroup or a substituted lower alkyl group) (provided that R₇ is ahydrogen atom when Z is O); or

R₂ is either a lower alkyl group or a substituted lower alkyl group and,at the same time, R₈ is a hydroxyl group (provided that the number ofcarbon atoms of the lower alkyl group is 3 or more when Z is O); or

at least one of R₁ to R₄ is a lower alkylcarbonyl group (provided thatthe number of carbon atoms of the lower alkyl group is 3 or more), acycloalkylcarbonyl group or a cycloalkenylcarbonyl group and, at thesame time, R₈ is a hydroxyl group; or

at least one of R₁ to R₄ is a cyano group; or

at least one of R₁ to R₄ is a halogen and, at the same time, Z is anyone of S, S═O and SO₂; or

R₅ and R₆ are hydroxyl groups and, at the same time, Z is S; or

at least one of R₁ to R₄ is —C(═NOR)CH₃ (wherein R is a hydrogen atom ora lower alkyl group), an optical isomer thereof, a conjugate thereof ora pharmaceutically acceptable salt thereof,

which comprises, in any order, the reaction steps of {circle around (1)}bonding a ring A to a ring C by the Ullmann reaction as shown in formula2 and {circle around (2)} bonding a ring A to a ring C by theFriedel-Crafts reaction or photoreation as shown in formula 3,

wherein

Q, S and W are each any substitutent;

U is C or N;

one of X and Y is a leaving group and the other is a nucleophilic group;and

Z is any one of O, S, SO and SO₂.

(18) The method stated in the above (17) further comprising at least onestep of the step of carbon atom increasing reaction, the step ofconversion reaction of a substituent, the step of introduction reactionof a substituent, the step of removal of the protection of asubstituent, the step of forming a salt and the step of performingoptical resolution. The order of these steps and step1 and step2 of (17)is not limited. A person skilled in the art can decide the orderconsidering a structure of the target compound and other conditions.

(19) A pharmaceutical composition comprising an effective amount of thecompound stated in any one of the above (1) to (16) and apharmaceutically acceptable carrier or diluent.

(20) The pharmaceutical composition stated in the above (19) whichutilizes the tracheal smooth muscles relaxing action of the compound.

(21) The pharmaceutical composition stated in the above (19) whichutilizes the inhibitory effect on airway hypersensitivity of thecompound.

(22) The pharmaceutical composition stated in the above (19) whichutilizes the inhibitory effect on inflammatory cells filtration of thecompound.

(23) The pharmaceutical composition stated in the above (19) which isused as the antiasthmatic drug.

(24) A compound of the following formula,

wherein Q is a lower alkyl group, an optical isomer thereof or a saltthereof.

(25) A compound of the following formula,

wherein

Q is a lower alkyl group; and

Q₁ to Q₅ which may be the same or different are each independently anyone selected from a hydrogen atom, a lower alkoxy group and a hydroxylgroup, an optical isomer thereof or a salt thereof.

Further, when the compounds and their salts described in the above (1)contain an asymmetric carbon atom in the structure, the optical activecompounds and the racemic compounds are also included in the scope ofthe present invention. In addition, the compounds and their saltsdescribed in the above (1) may be either the hydrates or nonhydrates andmay be the solvates.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the inhibitory effects of the compounds of thepresent invention on the immediate and late asthmatic responses inactively sensitized guinea pigs.

FIG. 2 is a graph showing the inhibitory effects of the compounds of thepresent invention on the immediate and late asthmatic responses inactively sensitized guinea pigs.

FIG. 3 is a graph showing the inhibitory effects of the compounds of thepresent invention on the number of inflammatory cells in thebronchoalveolar lavage fluid 24 hours after challenge with an antigen inactively sensitized guinea pigs.

FIG. 4 is a graph showing the inhibitory effects of the compound of thepresent invention on the airway reactivity to acetylcholine 22 to 26hours after challenge with an antigen in actively sensitized guineapigs.

BEST MODE FOR CARRYING OUT THE INVENTION

The term “halogen” as used in the specification of the presentapplication refers to any atom of fluorine, chlorine, bromine andiodine. Further, the term “trihalomethyl group” as used herein refers toa group in which three hydrogen atoms are substituted with halogenatoms, and these three halogen atoms may be all the same or may beconstituted of two or more different halogen atoms.

The term “lower alkyl group” as used herein refers to, for example, astraight-chain or branched chain C₁₋₆ alkyl group, and the C₁₋₆ alkylgroup includes, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. As the substituentwhich the “lower alkyl group” may have, one or more selected from, forexample, hydroxyl, amino, carboxyl, nitro, an aryl group, a substitutedaryl group, a mono- or di-lower alkylamino group (including, forexample, mono- or di-C₁₋₆ alkylamino such as methylamino, ethylamino,propylamino, dimethylamino and diethylamino), lower alkoxy (including,for example, C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy and hexyloxy),lower alkylcarbonyloxy (including, for example, C₁₋₆ alkylcarbonyloxysuch as acetoxy and ethylcarbonyloxy) and a halogen atom are employed.Further, the lower alkyl moiety in the “lower alkoxy group” as usedherein refers to the above described “lower alkyl group”.

The term “cycloalkyl group” as used herein refers to, for example, aC₃₋₈ cyclic alkyl group. The C₃₋₈ cycloalkyl group includes, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcyclooctyl. As the substituent which the “cycloalkyl group” may have,one or more selected from, for example, hydroxyl, amino, carboxyl,nitro, a mono- or di-lower alkylamino group (including, for example,mono- or di-C₁₋₆ alkylamino such as methylamino, ethylamino,propylamino, dimethylamino and diethylamino), a lower alkoxy (including,for example, C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy and hexyloxy),a lower alkylcarbonyloxy (including, for example, alkylcarbonyloxy suchas acetoxy and ethylcarbonyloxy) and a halogen atom are employed.

The term “cycloalkenyl group” as used herein refers to a cycloalkenylgroup having one or more double bonds on the ring moiety.

The term “lower alkenyl group” as used herein refers to, for example, astraight chain or branched chain C₂₋₆ alkenyl group. The C₂₋₆ alkenylgroup includes, for example, vinyl, allyl, 2-methylallyl, isopropenyl,2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl and 3-hexenyl.As the substituent which the “lower alkenyl group” may have, one or moreselected from, for example, hydroxyl, amino, carboxyl, nitro, mono- ordi-lower alkylamino group (including, for example, mono- or di-C₁₋₆alkylamino such as methylamino, ethylamino, propylamino, dimethylaminoand diethylamino), lower alkoxy such as methoxy, ethoxy, propoxy andhexyloxy), lower alkylcarbonyloxy (including, for example, C₁₋₆alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) and a halogenatom are employed.

The term “lower alkynyl group” as used herein refers to, for example, astraight chain or branched chain C₂₋₆ alkynyl group. The C₂₋₆ alkynylgroup includes, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl,2-pentynyl, 3-pentynyl, 2-hexynyl and 3-hexynyl. As the substituentwhich the “lower alkynyl group” may have, one or more selected from, forexample, hydroxyl, amino, carboxyl, nitro, mono- or di-lower alkylamino(including, for example, a mono- or di-C₁₋₆ alkylamino such asmethylamino, ethylamino, propylamino, dimethylamino and diethylamino),lower alkoxy (including, for example, C₁₋₆ alkoxy such as methoxy,ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy (including, forexample, C₁₋₆ alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) anda halogen atom are employed.

The lower alkyl moiety in the “lower alkylcarbonyl group” as used hereinrefers to the above described “lower alkyl group”.

As the substituent in the term “substituted amino group” as used herein,one or more selected from, for example, hydroxyl, carboxyl, nitro, mono-or di-lower alkyl (including, for example, mono- or di-C₁₋₆ alkyl suchas methyl, ethyl, n-propyl, isopropyl, dimethyl and diethyl), loweralkoxy (including, for example, C₁₋₆ alkoxy such as methoxy, ethoxy,propoxy and hexyloxy), lower alkylcarbonyloxy (including, for example,C₁₋₆ alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) and ahalogen atom are employed.

The term “acyl group” as used herein refers to —COR wherein R is any oneof a hydrogen atom, a lower alkyl group, a lower alkenyl group, a loweralkynyl group, a C₃₋₈ cycloalkyl group and a monocyclic or polycyclicaromatic ring or a hereocycle. The acyl moiety in the terms “acyloxygroup” and “acylamino group” as used herein refers to the abovedescribed acyl group. The substituent which the “acyl group” and the“acylamino group” may have refers to a substituent on the carbon atom ofR, and one or more selected from, for example, hydroxyl, amino,carboxyl, nitro, mono- or di-lower alkylamino (including, for example, amono- or di-C₁₋₆ alkylamino such as methylamino, ethylamino,propylamino, dimethylamino and diethylamino), lower alkoxy (including,for example, C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy and hexyloxy),lower alkylcarbonyloxy (including, for example, C₁₋₆ alkylcarbonyloxysuch as acetoxy and ethylcarbonyloxy) and a halogen atom are employed.

The term “aromatic ring” as used herein refers to a group of atomsremaining after removal of one hydrogen atom from an aromatichydrocarbon, that is, an aryl group. Particularly, C₆₋₁₄ alkyl groupsare preferred. Such C₆₋₁₄ alkyl groups that can be used include, forexample, phenyl, naphthyl, tolyl, xylyl, biphenyl, 1-naphthyl,2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl,2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenathryl, 1-azulenyl,2-azulenyl, 4-azulenyl, 5-azulenyl and 6-azulenyl. As the substituentwhich the “aromatic ring” may have, one or more selected from, forexample, lower alkyl, hydroxyl, amino, carboxyl, nitro, mono- ordi-lower alkylamino (including, for example, a mono- or di-C₁₋₆alkylamino such as methylamino, ethylamino, propylamino, dimethylaminoand diethylamino), lower alkoxy (including, for example, C₁₋₆ alkoxysuch as methoxy, ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy(including, for example, C₁₋₆ alkylcarbonyloxy such as acetoxy andethylcarbonyloxy), trihalomethane, trihalomethoxy, a halogen atom andaryl such as phenyl are used.

The term “heterocycle” as used herein refers to a group of atomsremaining after removal of one hydrogen atom from a 3- to 7-memberedheterocycle which contains one to four hetero atoms selected from, forexample, a nitrogen atom, an oxygen atom, and a sulfur atom in additionto carbon atoms. The heterocycle may be condensed. Exemplaryheterocycles include, for example, oxetane, tetrahydrofuran,tetrahydrothiophene, tetrahydropyran, pyrrole, azetidine, pyrrolidine,piperidine, piperazine, homopiperidine, morpholine, furan, pyridine,benzofuran and benzothiophene. As the substituent which the“heterocycle” may have, one or more selected from, for example,hydroxyl, amino, carboxyl, nitro, mono- or di-lower alkylamino(including, for example, a mono- or di-C₁₋₆ alkylamino such asmethylamino, ethylamino, propylamino, dimethylamino and diethylamino),lower alkoxy (including, for example, C₁₋₆ alkoxy such as methoxy,ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy (including, forexample, C₁₋₆ alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) anda halogen atom are used.

Further, examples of particularly preferred compounds in the presentinvention include the following compounds, their optical isomers,conjugated compounds and salts.

(1) Compounds in which two hydroxyl groups are present on ring C (R₅ toR₈) and a lower alkyl group is present in the 11-position (X-position).Specifically,7,8-dihydroxy-11-ethyl-10,11-dihydrodibenzo[b,f]thiepin-10-one,11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one,11-methyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one and thelike can be illustrated.

(2) Compounds in which two hydroxyl groups are present on ring C (R₅ toR₈) and a thio-lower alkyl group is present on ring A (R₁ to R₄).Specifically,7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-one,8-methylthio-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol and the like canbe illustrated.

(3) Compounds in which two hydroxyl groups are present on ring C (R₅ toR₈) and a heterocycle is bonded to ring A (R₁ to R₄). Specifically,7,9-dihydroxy-3-(2-furyl)-10,11-dihydrodibenzo[b,f]thiepin-10-one,7-(2-thienyl)-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol,7-(2-furyl)-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol and the like canbe illustrated.

As the salts of the compounds of the present invention, acid additionsalts whose acids are pharmaceutically or physiologically acceptableones are preferably employed. Such salts which can be used include, forexample, salts with inorganic acids (such as hydrochloric acid,phosphoric acid, hydrobromic acid and sulfuric acid); organic acids(suchas acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, lactic acid, citric acid, malic acid,oxalic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acidand benzenesulfonic acid); and alkalis (such as sodium, potassium,magnesium, calcium, ammonium, pyridine and triethylamine).

The conjugates of the compounds of the present invention include, forexamples, glucuronic acid conjugates and sulfuric acid conjugates of thecompounds represented by formula (1), their optical isomers and theirsalts.

Next, the method for the preparation of the compounds of the presentinvention or their salts will be described.

The tricyclic condensed heterocyclic compound of the present inventionis a 6-7-6-membered tricyclic compounds consisting of three rings of A,B and C as shown in formula (4) below.

The skeleton of this compound can be prepared by the combination ofbonding of ring A to ring C by the Ullmann reaction and bonding of ringA to ring C by the Friedel-Crafts reaction or photoreaction. Dependingon the starting material and the target compound, it is necessary to adda carbon atom increasing reaction. Furthermore, if necessary or desired,the target compound can be obtained by carrying out a substituentintroduction reaction and a substituent conversion reaction.

For example, the first step is to bond ring A to ring C by the Ullmannreaction. Then, the second step (carbon atom increasing reaction) is toincrease W of carbon atoms to make ring B 7-membered. Furthermore, thethird step is to form ring B by the Friedel-Crafts reaction. The fourthstep (substituent introduction reaction) is to introduce a necessarysubstituent such as a halogen and a lower alkyl group into the tricycliccompound thus formed.

As regards the introduction of a substituent, it is possible tointroduce the substituent either into the starting material of the firststep or in the middle of the carbon atom increasing reaction of thesecond step and thus, the introduction of the substituent can beselected by taking the type of the target compound or the like intoconsideration when the occasion demands. Furthermore, if necessary ordesired, the carbonyl group of the 10-position can be reduced or thesubstituent, OR (for example; OCH₃), can be converted into OH by thereaction of removing the protection.

Now the reaction scheme of each step will be illustrated.

{circle around (1)} Ullmann Reaction

wherein

one of X and Y is a leaving group; and the other is a nucleophilicagent.

{circle around (2)}-1 Friedel-Crafts Reaction

{circle around (2)}-2 Photoreaction

{circle around (3)} Carbon Atom Increasing Reaction

{circle around (4)} Conversion Reaction of Halogen to another FunctionalGroup

{circle around (5)} Introduction Reaction of Alkyl Group orAlkylcarbonyl Group

{circle around (6)} Conversion Reaction at 10-Position

{circle around (7)} Reaction of Deprotection

The above mentioned reaction scheme of each step will be explained asfollows.

{circle around (1)} Ullmann Reaction

Ring A having a necessary substituent and a substituted benzenecorresponding to ring C are formed into a coupled compound by theUllmann reaction. The leaving group in the Ullmann reaction which can beused includes, for example, a halogen (for example, chlorine, bromine oriodine), C₆₋₁₀ arylsulfonyloxy (for example, benzenesulfonyloxy orp-toluenesulfonyloxy) and C₁₋₄ alkylsulfonyloxy (for example,methanesulfonyloxy) and above all, a halogen (for example, chlorine,bromine or iodine) is preferred. The nucleophilic side which can be usedincludes, for example, a precursor having a functional group containingoxygen or sulfur and above all, a substituted phenol, a substitutedthiophenol and a substituted disulfide are preferred.

{circle around (2)} Friedel-Crafts Reaction or Photoreaction

The reaction of further bonding ring A to ring C can use a method whichis conventionally carried out as the Friedel-Crafts reaction. Forexample, the methods of “Comprehensive Organic Synthesis: TheIntramolecular Aromatic Friedel-Crafts Reaction”, Vol. 2, pp753 (1991),J. Org. Chem., 52, 849 (1987) and Synthesis, 1257 (1995) or the onescorresponding thereto can be used. Further, by using thephotocyclization method as shown in Japanese Patent Publication (Kokai)No. Hei 10-204079/1998) or the one corresponding thereto, a substitutedacetophenone compound can be directly led to a cyclized compound.Further, the order of the Ullmann reaction and these reactions can alsobe changed.

{circle around (3)} Carbon Atom-Increasing Reaction

When a substituted phenyl acetate derivative is used in the Ullmannreaction, it can be directly led to a cyclized compound but when asubstituted benzoic acid derivative is used, the moiety corresponding toring B is subjected to a carbon atom-increasing reaction. In thisinstance, a substituted benzoic acid derivative can be led to thesubstituted phenyl acetate via the substituted benzyl alcohol compound,the substituted benzyl halide compound and the substituted benzylnitrile compound. Further, the substituted benzyl halide compound canalso be directly led to the substituted phenyl acetate with carbondioxide. By the Willgerodt reaction, the substituted acetophenonecompound is formed into the substituted morpholine compound which can bethen led to the substituted phenyl acetate.

{circle around (4)} Conversion Reaction of Halogen to another FunctionalGroup

The introduction reaction of a heterocycle, a substituted phenyl ring ora lower alkyl group can be carried with palladium by using the methodsof Chem. Rev., 95, 2457 and “Organic Reactions”, Vol. 50 (1997) or onecorresponding thereto.

{circle around (5)} Reaction of Introduction of Alkyl Group orAlkylcarbonyl Group

The introduction of an alkyl group such as an ethyl group can be carriedout in the presence of a base for the cyclized compound in an anhydroussolvent in the presence of an alkyl halogenating agent or an alkali withthe use of a phase transfer catalyst and an alkyl halogenating agent.Further, the alkyl group can be introduced into either an intermediateof the carbon atom increasing reaction before cyclization or thestarting material before the Ullmann reaction. The introduction of analkylcarbonyl group can be carried out by using the Friedel-Craftsreaction.

{circle around (6)} Conversion Reaction at 10-Position

The carbonyl group of the cyclized compound is reduced to an alcoholcompound of the cyclized compound which is then formed into the olefiniccompound by dehydration reaction, and this oleinic compound can be ledto the decarbonylated compound by catalytic reduction. Further, thealcohol compound of the cyclized compound is subjected to the reaction{circle around (7)} of Deprotection to form the olefinic compound whichcan be then led to the decarbonylated compound by reduction.Alternatively, the cyclized compound can be directly led to thedecarbonylated compound by Wolff-Kishner reduction.

{circle around (7)} Reaction of Deprotection

The reaction of deprotection can be carried out with a pyridine salt ora boron halide.

The preparation of the compounds of the present invention is preferablycarried out in a solvent, and such a solvent that can be used include,for example, aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran and dioxane; amides suchas dimethylformamide and dimethylacetamide; sulfoxide such as dimethylsulfoxide; nitrites such as acetonitrile; N-methyl-2-pyrrolidone andanhydrous solvents thereof. The reaction temperature is −78° C. to 200°C., and the reaction time is 30 minutes to several days, and thereaction is advantageously carried out under a stream of nitrogen orargon. The reaction product can be isolated and purified by known meanssuch as solvent extraction, acidity or alkalinity conversion,transdissolution, salting out, crystallization, recrystallization andchromatography.

In the method of the present invention, when the substituent is an aminogroup, the amino group is preferably protected, and a protective groupwhich is commonly used in the field of peptide chemistry and the likecan be used, and a protective group of the type which forms an amide,such as formyl, acetyl and benzoyl; a protective group of the type whichforms a carbamate, such as tert-butoxycarbonyl and benzyloxycarbonyl; aprotective group of the imino type such as dimethylaminomethylene,benzylidene, p-methoxybenzylidene and diphenylmethylene are preferablyused. Preferred protective groups which can be used are, for example,formyl, acetyl and dimethylaminomethylene. Further, when the productobtained in the above described reactions has a protective group, theprotective group can be removed by the conventional method. For example,the protective group can be removed by hydrolysis with an acid or a baseor by procedure of deprotection such as catalytic reduction or the like.

Further, when the compound of the present invention has an asymmetriccarbon, an optical isomer can be obtained by using conventionally knownvarious optically resolving methods such as an optical isomer resolvingcolumn.

In addition, the compounds of the present invention or theirpharmaceutically or physiologically acceptable salts thereof have a widerange of pharmacological actions such as the excellent relaxing actionof tracheal smooth muscles, the inhibition of airway hypersensitivityand the inhibition of infiltration of inflammatory cells into the airwayand can be used as safe antiasthmatic drugs and the like for mammals(humans, mice, dogs, rats, cattle and the like). Specifically, when theyare used as antiasthmatic drugs for humans, the dose may vary dependingon the age, weight, symptom of disease, route of administration,frequency of administration and the like, and they are administered witha dose of 0.1 to 100 mg/kg daily, preferably 1 to 50 mg/kg daily once ordividedly twice. The route of administration may be either oral orparenteral.

The compounds of the present invention or their salts may beadministered as the bulk drug but they are usually administered in theform of preparations with a drug carrier. As concrete examples, tablets,capsules, granules, fine granules, powders, syrups, injections,inhalants and the like are employed. These pharmaceutical preparationscan be prepared according to conventional techniques. As carriers oforal preparations, the substance which is conventionally employed in thefield of pharmaceutical preparation, such as starch, mannitol,crystalline cellulose and sodium carboxymethyl cellulose can be used. Ascarriers for injections, distilled water, a physiological saline,glucose solution, a transfusion and the like can be used. Otheradditives which are commonly employed in pharmaceutical preparations cansuitably be added.

REFERENTIAL EXAMPLES

Examples of the method for preparing the starting material substances ofthe present invention and each of the above described reactions will beexplained below but the present invention is not limited to them and maybe changed without departing from the scope of the present invention.The elution in the chromatography of Referential Example was carried outunder observation by thin-layer chromatography (TLC) unless expresslystated. In the TLC observation, “60F₂₅₄” of Merck was used as the TLCplate and as the developing solvent, a solvent which was used as theeluting solvent in column chromatography was used. Further, an UVdetector was employed in detection. As the silica gel for the columnchromatography, “Silica Gel 60” (70 to 230 mesh) of Merck or“Microsphere Gel D75-60A” of Asahi Glass was used. The term “roomtemperature” means from about 10° C. to about 35° C.

Referential Example 1

Method of Preparing 4-Bromo-2-chlorobenzoic Acid (3)

Synthesis of 4-Amino-2-chlorobenzoic Acid (2)

In ethanol (250 mL) was dissolved 100 g (F.W. 201.57, 496 mmol) of2-chloro-4-nitrobenzoic acid (1) and after replacing with argon, a 10%palladium carbon catalyst (4.0+1.5 g) was added thereto. After replacingwith hydrogen, the mixture was stirred at room temperature for 72 hours.The formed crystal was dissolved with acetone and filtered to remove thecatalyst. The solvent was distilled under reduced pressure toquantitatively obtain 88 g of the target 4-amino-2-chlorobenzoic acid(2).

Melting point: 215-217° C.

Synthesis of 4-Bromo-2-chlorobenzoic Acid (3)

Eighty-eight grams (F.W. 171.58, 513 mmol) of 4-amino-2-chlorobenzoicacid (2), 48% hydrobromic acid (304 mL) and water (304 mL) were heatedat 120° C. for one hour and dissolved to form a hydrobromate salt. Understirring, the solution was cooled (ice-sodium chloride), and an aqueoussolution (water, 250 mL) of 44.4 g (F.W. 69.00, 643 mmol) of sodiumnitrite was added thereto while maintaining 5° C. or below.

In a beaker 120.8 g (F.W. 80.79, 2.83 mmol) of copper bromide in 48%hydrobromic acid (331 mL) was made 0° C. and the prepared diazonium saltsolution was slowly added thereto with stirring so as not to foam. Aftercompletion of the addition, the resulting solution was heated in a hotwater bath until the generation of nitrogen ceased. The reactionsolution was cooled by standing and then, extracted with ethyl acetate.The extract was treated according to the conventional method to obtain88.3 g (73%) of a desired 4-bromo-2-chlorobenzoic acid (3).

Melting Point: 152-160° C. IR (KBr)ν_(max) cm⁻¹: 3090, 1682, 1578 ¹H NMR(400 MHz, CDCl₃) δ: 7.50 (1H, dd, J=8.5, 2.0 Hz, Ar—H), 7.69 (1H, J=2Hz, Ar—H), 7.89 (1H, J=8.5 Hz, Ar—H).

Referential Example 2

Method of Preparing of Di-(3,5-dimethoxyphenyl) disulfide (9)

To a suspension of 25.0 g (F.W. 153.18, 163.2 mmol) of3,5-dimethoxyaniline (4) in 500 mL of water was added 40.8 mL (489.6mmol) of concentrated hydrochloric acid to completely dissolve thehydrochloride by stirring and heating. To the resulting solution wasadded 400 mL of water and then, ice-cooled. While maintaining thereaction temperature (inner temperature) at 5° C. or below andvigorously stirring, a solution of 11.8 g (F.W. 69.00, 171.4 mmol) ofsodium nitride in 40 mL of water was carefully added to the resultingsolution. The obtained solution was stirred at the same temperature forabout 30 minutes to prepare a dizaonium salt solution.

A suspension of 680.5 g (F.W. 160.30, 4243.2 mol) of potassiumxanthogenate (6) in 550 mL of water was completely dissolved by raisingthe temperature to 65 to 70° C. to prepare a potassium xanthogenatesolution.

To this solution maintained at 65 to 70° C. was slowly added dropwisethe dizaonium salt solution maintained at 5° C. of below over 30minutes. This procedure was repeated four times.

The resulting solution was stirred at 65 to 70° C. for about one hourand then, cooled to room temperature by standing. The resulting solutionwas extracted with ethyl acetate three times. The extract was washedwith 1N sodium hydroxide, water and a saturated sodium chloride aqueoussolution in the order named. After drying with anhydrous sodium sulfate,the solvent was removed under reduced pressure to obtain a crude product(7). By column chromatography (developing solvent; hexane:ethylacetate=7:1) 122.31 g of product (7)[and a mixture with compound (9)]was obtained.

In 450 mL of ethanol was dissolved 85.7 g of product (7)[and a mixturewith compound (9)] and then, 50 mL of water and 200.0 g (F.W. 56.11,4986.0 mmol) of potassium hydroxide were added thereto. The reactionsolution was stirred under refluxing for 10 minutes. After havingconfirmed the absence of compound (7) by TLC, the reaction solution wascooled by standing and neutralized with 3N hydrochloric acid. Underreduced pressure, ethanol was distilled off and then, the residue wasextracted with ethyl acetate three times and the extract was washed witha saturated sodium chloride aqueous solution. To the organic layer wasadded 25.0 g (F.W. 79.54, 314.3 mmol) of copper (II) oxide (powder) andstirred at room temperature while bubbling air (or oxygen) thereintountil thiol (8) disappeared. After removing insolubles by filtration,water was added to the solution thus obtained and the resulting solutionwas extracted with ethyl acetate three times and the extract was washedwith 1N hydrochloric acid, water and a saturated sodium chloride aqueoussolution in the order named. After drying with anhydrous sodium sulfate,the solvent was removed under reduced pressure to obtain 53.65 g of acrude product (9). This crude product (9) was purified by columnchromatography (developing solvent; hexane:ethyl acetate=19:1) to obtain34.87 g (pure) (F.W.338.44, 103.0 mmol) and 11.05 g (crude) of disulfide(9) in 41% yield.

Melting Point: 152-160° C. IR (KBr)ν_(max) cm⁻¹: 3090, 1682, 1578 ¹H NMR(400 MHz, CDCl₃) δ: 7.50 (1H, dd, J=8.5, 2 Hz, Ar—H), 7.69 (1H, J=2 Hz,Ar—H), 7.89 (1H, J=8.5 Hz, Ar—H)

Referential Example 3

Method of Preparing of Di-(3,4-dimethoxyphenyl) disulfide

To 100 g of veratrole (10) was added 500 mL of anhydrous methylenechloride and stirred at 0° C. To this solution was added 235 mL ofchlorosulfonic acid over one hour and stirred at 50° C. for 30 minutes.The resulting solution was added dropwise to 1.5 L of methanol at 0° C.over 40 minutes and then, 290 mL of hydrochloric acid and 570 g ofstannous chloride were added thereto at room temperature and stirred fortwo hours. The obtained solution was concentrated under reduced pressureto half the volume and then, the resulting solution was extracted withtoluene and the organic layer was washed with 12% hydrochloric acid,water and a saturated sodium chloride solution in the order named, andsubsequently dried with anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure. The residue was dissolved in ethylacetate and then, 20 g of cupric oxide was added thereto and stirredwhile bubbling air. The catalyst was filtered and the filtrate waswashed with ethyl acetate and then, recrystallized from ethylacetate-hexane to obtain a desired compound (11). (Total yield 21%).

EM-MS: 338 (M⁺), 169 (Base) NMR (CDCl₃): 3.83 (6H, s), 3.87 (6H, s),6.79 (2H, d, J=8.3 Hz), 7.01 (2H, d, J=2.1 Hz), 7.05 (2H, dd, J=2.1, 8.3Hz).

Referential Example 4

Method of Preparing 8-Bromo-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (21)

Synthesis of Carboxylic Acid (14)

To a mixture of 30.0 g (F.W. 235.46, 127 mmol) of5-bromo-2-chlorobenzoic acid (12), 21.6 g (F.W. 154.165, 140 mmol) of3,5-dimethoxyphenol (13), 35.3 g (F.W. 138.21, 325.6 mmol) of potassiumcarbonate and 180 mL of N-methyl-2-pyrrolidone was added benzene (100mL) and the resulting solution was dried by a Dean-Stark water separator(140-170° C.) for three hours and then, 1.59 g (F.W. 63.55, 25.0 mmol)of copper (powder) and 6.05 g (F.W. 190.45, 25.0 mmol) of copper (I)iodide were added thereto and stirred at 120° C. for 1.5 hours. Thisreaction mixture was cooled by standing and ice water and ethyl acetatewere added thereto and then, the obtained solution was made pH 2 withconcentrated hydrochloric acid and filtered. The organic layer wasseparated and then, thoroughly washed with water and subjected tosalting out with a saturated sodium chloride aqueous solution. Afterdrying with anhydrous magnesium sulfate and concentration, the residuewas recrystallized from benzene to obtain 25.47 g of carboxylic acid(14). The mother liquor was purified by column chromatography (silicagel, water content of 6%; 250 g, ethyl acetate:hexane=1:2) to obtain4.58 g of crystals. Total yield: 30.05 g (67%)+9.23 g of mother liquor(purity 40%) (TLC; ethyl acetate:hexane=1:2 or 1:1).

MS(EI): 354, 352, 269 NMR (CDCl₃): 3.76 (2H, s, CH₂), 3.77 (6H, s,CH₃×2), 6.22 (2H, d, J=2.5 Hz, Ar—H), 6.33 (1H, d, J=2.5 Hz, Ar—H), 6.85(1H, d, J=8.5 Hz, Ar—H), 7.57 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 8.26 (1H,d, J=2.2 Hz, Ar—H).

Synthesis of Alcohol (15)

To a solution of 21.5 g (F.W. 353.168, 60.9 mmol) of carboxylic acid(14) in 75 mL of tetrahydrofuran was added potionwise 2.65 g (F.W.37.83, 70.05 mmol) of sodium borohydride at room temperature and then,9.49 mL (F.W. 141.93, d=1.154, 77.16 mmol) of boron trifluoride diethyletherate was added dropwise thereto. The resulting solution was stirredat room temperature for one hour. A 200 mL of ice water was slowly addedto the reaction solution. The resulting solution was extracted withethyl acetate and the extract was washed with a saturated sodiumchloride aqueous solution three times. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was recrystallized from benzene-diisopropyl ether to obtain19.04 g (98%) of alcohol (15). (TLC; ethyl acetate:hexane=1:4).

MS(EI): 340, 338, 291, 289 NMR (CDCl₃): 3.75 (6H, s, CH₃×2), 4.70 (2H,s, CH₂), 6.02 (2H, d, J=2.5 Hz, Ar—H), 6.07 (1H, d, J=2.5 Hz, Ar—H),6.85 (1H, d, J=8.5 Hz, Ar—H), 7.39 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 7.64(1H, d, J=2.2 Hz, Ar—H).

Synthesis of Chloride (16)

By azeotropy with benzene, 20.0 g (F.W. 339.185, 62.6 mmol) of alcohol(15) was dried. A 40 mL of benzene and 10 mL of methylene chloride towhich 5.63 mL (F.W. 118.97, d=1.631, 76.7 mmol) of thionyl chloride and5.6 mL of methylene chloride were added at 0° C. were added to the driedalcohol to give a mixture. The mixture was stirred at the sametemperature for 30 minutes. The reaction solution was further stirred atroom temperature overnight. To the reaction mixture was added ice waterand the resulting solution was extracted with ethyl acetate and theextract was washed with water and then with a saturated sodium chlorideaqueous solution. After drying with anhydrous magnesium sulfate, thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 14.03 g (65%) of chloride (16). (TLC;ethyl acetate:hexane=1:4).

NMR (CDCl₃): 3.75 (6H, s, CH₃×2), 4.49(2H, s, CH₂), 6.16 (2H, d, J=2.5Hz, Ar—H), 6.25 (1H, d, J=2.5 Hz, Ar—H), 6.78 (1H, d, J=8.7 Hz, Ar—H),7.35 (1H, dd, J=8.7, 2.4 Hz, Ar—H), 7.57(1H, d, J=2.4 Hz, Ar—H).

Synthesis of Nitrile Compound (17)

In 30 mL of dimethyl sulfoxide was dissolved 27.9 g (F.W. 357.631, 78.0mmol) of chloride (16). To this solution was added 5.49 g (F.W. 49.01,112.0 mmol) of sodium cyanide and stirred at 80° C. for one hour. Undercooling with ice water, water was added to the reaction solution andthen, the resulting solution was extracted with ethyl acetate threetimes. The extract was washed with water and then with a saturatedsodium chloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue wasrecrystallized from methylene chloride-hexane to obtain 16.91 g (65%) ofnitrile compound (17). (TLC; ethyl acetate:hexane=1:4).

MS(EI): 349, 347 NMR (CDCl₃): 3.70(2H, s, CH₂), 3.74 (3H, s, CH₃), 3.75(3H, s, CH₃), 6.11 (2H, d, J=2.5 Hz, Ar—H), 6.26(1H, d, J=2.5 Hz, Ar—H),6.81 (1H, d, J=8.5 Hz, Ar—H), 7.40(1H, dd, J=8.5, 2.2 Hz, Ar—H ),7.62(1H, d, J=2.2 Hz, Ar—H).

Synthesis of Phenylacetic Acid (18)

To 14.00 g (F.W. 348.196, 40.0 mmol) of nitrile compound (17) were added33.6 mL of ethanol and 33.6 mL of a 6N sodium hydroxide aqueous solution[8.06 g (F.W. 40.00, 201.5 mmol) of sodium hydroxide being dissolved inwater] and stirred at 110° C. overnight. To the reaction solution wasadded ice and the resulting solution was made pH 2 with concentratedhydrochloric acid. The reaction solution thus obtained was extractedwith ethyl acetate and the extract was washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was completely removed and the residuewas crystallized from benzene-hexane to obtain 13.33 g (90%) ofphenylacetic acid (18). (TLC; ethyl acetate:hexane=1:2 or 1:1).

NMR (CDCl₃): 3.70 (3H, s, CH₃), 3.90 (3H, s, CH₃), 3.95 (1H, s, CH₂),6.26 (1H, d, J=2.5 Hz, Ar—H), 6.46 (1H, d, J=2.5 Hz, Ar—H), 7.08 (1H, d,J=8.5 Hz, Ar—H), 7.33 (1H, dd, J=8.5, 2.3 Hz, Ar—H ), 7.41 (1H, d, J=2.3Hz, Ar—H), 12.91 (1H, s, OH).

Synthesis of Cyclized Compound (19)

To 11.75 g (F.W. 367.195, 32.0 mmol) of carboxylic acid (18) was added60 mL of methanesulfonic acid to dissolve carboxylic acid (18). Theresulting solution was stirred at 40° C. for three days. To the reactionsolution was added 300 mL of ice water to deposit a cyclized compound.The deposited cyclized compound was separated by filtration andextracted with ethyl acetate and treated by the conventional method toobtain a crude product. This crude product was recrystallized fromhexane-methylene chloride to obtain 6.0 g (54%) of cyclized compound(19). (TLC; ethyl acetate:hexane=1:2).

MS(EI): 349, 347, 269 NMR (CDCl₃): 3.84 (3H, s, CH₃), 3.90 (3H, s, CH₃),3.95 (1H, s, CH₂), 6.26 (1H, d, J=2.5 Hz, Ar—H), 6.46 (1H, d, J=2.5 Hz,Ar—H), 7.08 (1H, d, J=8.5 Hz, Ar—H), 7.33 (1H, dd, J=8.5, 2.3 Hz, Ar—H),7.41 (1H, d, J=2.3 Hz, Ar—H), 12.91 (1H, s, OH).

Synthesis of 2-Bromo-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one(20)

To 395 mg (F.W. 349.18, 1.13 mmol) of dimethoxylated compound (19) wasadded 2.0 g of pyridine hydrochloride and stirred at 195° C. for 1.5hours under heating and then, ice water was slowly added. The resultingsolution was extracted with ethyl acetate and the extract was washedwith 1N hydrochloric acid, water and a saturated sodium chloride aqueoussolution in the order named. After drying with anhydrous magnesiumsulfate, the dried extract was concentrated. The residue was purified bysilica gel column chromatography (developing solvent; ethylacetate:hexane=1:2). Furthermore, the product thus obtained wasrecrystallized from diisopropyl ether-hexane to obtain 223 mg (61%) ofthe title compound. (TLC; ethyl acetate:hexane=1:2).

Melting Point: 194-195° C. MS(EI): 322, 320, 241 NMR (CDCl₃): 4.03 (2H,s, CH₂), 5.88 (1H, s, OH), 6.17 (1H, d, J=2.5 Hz, Ar—H), 6.35 (1H, d,J=2.5 Hz, Ar—H), 7.10 (1H, d, J=8.5 Hz, Ar—H), 7.36 (1H, dd, J=8.5, 2.3Hz, Ar—H), 7.43 (1H, d, J=2.3 Hz, Ar—H), 12.91 (1H, s, OH).

Synthesis of 8-Bromo-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (21)

To 2.00 g (F.W. 321.126, 6.23 mmol) of dimethoxylated compound (19) wasadded 50 mL of methanol and stirred. The obtained suspension was cooledto 0° C. Thereto 500 mg of sodium borohydride was dividedly addedseveral times. The reaction solution was returned to room temperatureand stirred for one hour. To the reaction solution was added dilutehydrochloric acid to stop the reaction, and methanol was distilled offunder reduced pressure. The resulting reaction solution was partitionedwith ethyl acetate. The organic layer was washed with water and thenwith a saturated sodium chloride aqueous solution, and subsequentlydried with anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure to obtain an oily substance, and 10 g of pyridinehydrochloride was added to the oily substance and stirred at 200° C. fortwo hours under heating. After completion of the reaction, the reactionsolution was partitioned with ethyl acetate and dilute hydrochloricacid. The organic layer was washed with water and then with a saturatedsodium chloride aqueous solution, and subsequently dried with anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(developing solvent; hexane:ethyl acetate=1:1). The oily substance thusobtained was dissolved in 20 mL of ethyl acetate. To the resultingsolution was added 100 mg of palladium (IV) oxide to effect catalyticreduction at room temperature for three days. After completion of thereaction, the reaction solution was filtered and concentrated and theresidue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=2:1). The product thus obtained wasrecrystallized from chloroform-hexane to obtain the title compound(901.0 mg, 52.2%) as orange plates.

Melting Point: 173.8-175.8° C. NMR (DNSO-d₆): 2.74 (2H, t, J=6.3 Hz,CH₂), 2.99 (2H, t, J=6.3 Hz, CH₂), 6.05 (1H, d, J=2.3 Hz, Ar—H), 6.10(1H, d, J=2.3 Hz, Ar—H), 7.04 (1H, d, J=8.5 Hz, Ar—H), 7.32 (1H, dd,J=8.5, 2.5 Hz, Ar—H), 7.42 (1H, d, J=2.5 Hz, Ar—H), 9.19 (1H, s, Ph—OH),9.39 (1H, s, Ph—OH).

Referential Example 5

Method of Preparing 7-Bromo-10,11-dihydrodibenz[b,f]-oxepin-1,3-diol(29)

Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)benzoic Acid (22)

To a mixture of 88.3 g (F.W. 235.46, 375 mmol) of4-bromo-2-chlorobenzoic acid (3), 57.8 g (F.W. 154.165, 375 mmol) of3,5-dimethoxyphenol (13), 93.2 g (F.W. 138.21, 670 mmol) of potassiumcarbonate and 400 mL of N-methyl-2-pyrrolidone was added benzene (200mL), and the resulting solution was dried by a Dean-Stark waterseparator (140-170° C.) for three hours and then, 6.0 g (F.W. 63.55,93.7 mmol) of copper (powder) and 17.8 g (F.W. 190.45, 93.7 mmol) ofcopper (I) iodide were added thereto and stirred at 120° C. for 30minutes. This reaction mixture was cooled by standing and ice water andethyl acetate were added thereto and then, the obtained solution wasmade pH 2 with concentrated hydrochloric acid and filtered. The organiclayer was separated and then, thoroughly washed with water and subjectedto salting out with a saturated sodium chloride aqueous solution. Theresulting solution was dried with anhydrous magnesium sulfate andconcentrated and the residue was purified by silica gel columnchromatography (developing solvent; ethyl acetate:hexane=1:3) andrecrystallized from ethyl acetate-hexane to obtain 75.4 g (57%) adesired compound (20). (TLC; ethyl acetate:hexane=1:2 or 1:1).

Melting Point: 112-117° C. UV (EtOH)λ_(max)(ε): 292 (2000) nm IR (KBr)ν_(max) cm⁻¹: 3411, 1699, 1605 ¹H NMR (400 MHz, CDCl₃) δ: 3.75 (2H, s,CH₂), 3.77 (6H, s, CH₃×2), 6.23 (1H, d, J=2.1 Hz, Ar—H), 6.34 (1H, d,J=2.1 Hz, Ar—H), 7.09 (2H, m, Ar—H), 7.32 (1H, m, Ar—H), 7.98 (1H, m,Ar—H).

MS(EI) m/z: 354, 352, 309, 307.

Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)benzyl Alcohol (23)

To a solution of 75.4 g (F.W. 353.168, 213 mmol) of4-bromo-2-(3,5-dimethoxyphenoxy)benzoic acid (22) in 300 mL oftetrahydrofuran was added 8.9 g (F.W. 37.83, 235 mmol) of sodiumborohydride portionwise at room temperature and then, 31 mL (F.W.141.93, d=1.154, 252 mmol) of boron trifluoride diethyl etherate wasadded thereto dropwise. The resulting solution was stirred at roomtemperature for one hour. To this reaction solution was added 200 mL ofice water slowly. The resulting solution was extracted with ethylacetate and the extract was washed with a saturated sodium chlorideaqueous solution three times. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue wasrecrystallized from benzene-diisopropyl ether to obtain 46.6 g (64%) ofalcohol (23). (TLC; ethyl acetate:hexane=1:4).

MS(EI) m/z: 340, 338.

Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)benzyl Bromide (24)

In an argon atmosphere, 4.7 mL (F.W. 270.70, d=2.850, 49.5 mmol) ofphosphorus tribromide was added to a solution of 46 g (F.W. 339.19, 135mmol) of alcohol (23) in 100 mL of methylene chloride at 0° C. andstirred at room temperature for 30 minutes. To the reaction mixture wasadded ice water and the resulting solution was further stirred at roomtemperature for 30 minutes. The obtained solution was extracted withethyl acetate and the extract was washed with water and then with asaturated sodium chloride aqueous solution. The resulting extract wasdried with anhydrous magnesium sulfate and then, concentrated. Theresidue was purified by silica gel column chromatography (developingsolvent; ethyl acetate:hexane=1:5) to obtain 44.6 g (84%) of a bromide(24). (TLC; ethyl acetate:hexane=1:4).

Synthesis of 4-Bromo-2-(3.5-dimethoxyphenoxy)benzyl Nitrile (25)

In 50 mL of dimethyl sulfoxide was dissolved 44.6 g (F.W. 357.631, 111mmol) of bromide (24). To this solution was added 8.15 g (F.W. 49.01,166 mmol) of sodium cyanide and stirred at 80° C. for one hour. Undercooling with ice water, to the reaction solution was added water andthen, the resulting solution was extracted with ethyl acetate threetimes. The extract was washed with water and then with a saturatedsodium chloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 34.5 g (89%) of nitrile compound (25).(TLC; ethyl acetate:hexane=1:4).

¹H NMR (400 MHz, CDCl₃) δ: 3.70(2H, s, CH₂), 3.77 (6H, s, CH₃×2), 6.14(1H, d, J=2.1 Hz, Ar—H), 6.28 (1H, d, J=2.1 Hz, Ar—H), 7.02 (1H, m,Ar—H), 7.15 (1H, m, Ar—H), 7.21 (1H, m, Ar—H) MS(EI) m/z: 349, 347, 269.

Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)phenylacetic Acid (26)

To 34.5 g (F.W. 348.196, 99.1 mmol) of nitrile compound (25) were added83 mL of ethanol and 83 mL [19.9 g (F.W. 40.00, 497 mmol) of sodiumhydroxide] of a 6N sodium hydroxide aqueous solution and stirred at 110°C. overnight. To the reaction solution was added ice and the obtainedsolution was made pH 2 with concentrated hydrochloric acid. The reactionsolution thus obtained was extracted with ethyl acetate and the extractwas washed with water and then with a saturated sodium chloride aqueoussolution. After drying with anhydrous magnesium sulfate, the solvent wascompletely removed and the residue was purified by silica gel columnchromatography (developing solvent; ethyl acetate:hexane=2:3) andcrystallized from ethyl acetate-hexane to obtain 27.3 g (75%) ofcarboxylic acid (26). (TLC; ethyl acetate:hexane=1:2 or 1:1).

Melting Point: 121.9-123.6° C. UV (EtOH)λ_(max)(ε): 272 (2200)nm IR(KBr)ν_(max) cm⁻¹: 2954, 1705, 1606, 1576 ¹H NMR (400 MHz, CDCl₃) δ:3.60 (2H, s, CH₂), 3.60 (6H, s, CH₃×2), 6.13 (1H, d, J=2.1 Hz, Ar—H),6.25 (1H, d, J=2.1 Hz, Ar—H), 7.02 (1H, m, Ar—H), 7.15 (1H, m, Ar—H),7.21 (1H, m, Ar—H), MS(EI) m/z: 368, 366.

Synthesis of 3-Bromo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one(27)

To 27.3 g (F.W. 367.195, 74.3 mmol) of carboxylic acid (26) was added140 mL of methanesulfonic acid to dissolve carboxylic acid (26). Thissolution was stirred at 40° C. for three days. To the resulting reactionsolution was added 300 mL of ice water to deposit a cyclized compound.The cyclized compound was separated by filtration and extracted withethyl acetate and treated according to the conventional method to obtaina crude product. This crude product was purified by silica gel columnchromatography (developing solvent; ethyl acetate:hexane=1:2) andrecrystallized from hexane-ethyl acetate to obtain 17.1 g (66%) ofcyclized compound (27). (TLC; ethyl acetate:hexane=1:2).

Melting Point: 95-103° C. UV (EtOH)λ_(max)(ε): 272 (2800)nm IR(KBr)ν_(max) cm⁻¹: 2977, 1679, 1604 ¹H NMR (400 MHz, CDCl₃) δ: 3.84 (3H,s, CH₃), 3.88 (3H, s, CH₃), 3.95 (2H, s, CH₂), 6.27 (1H, d, J=2.1 Hz,Ar—H), 6.47 (1H, d, J=2.1 Hz, Ar—H), 7.15 (1H, m, Ar—H), 7.30 (1H, m,Ar—H), 7.40 (1H, m, Ar—H), MS(EI) m/z: 350, 348

Synthesis of 3-Bromo-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one(28)

To 395 mg (F.W. 349.18, 15.75 mmol) of dimethoxylated compound (27) wasadded 2.0 g of pyridine hydrochloride and stirred at 195° C. for 1.5hours and then, ice water was slowly added thereto. The resultingsolution was extracted with ethyl acetate and the extract was washedwith 1N hydrochloric acid, water and a saturated sodium chloride aqueoussolution in the order named. The extract thus washed was dried withanhydrous magnesium sulfate and then, concentrated. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:2). Furthermore, the product thus obtained wasrecrystallized from dioxane and dioxane-hexane to obtain 223 mg (61%) ofthe title compound. (TLC; ethyl acetate:hexane=1:2).

Melting Point: 194-195° C. ¹H NMR (400 MHz, CDCl₃) δ: 4.03 (2H, s, CH₂),6.09 (1H, d, J=2.1 Hz, Ar—H), 6.39 (1H, d, J=2.1 Hz, Ar—H), 7.43 (2H, m,Ar—H), 7.64 (1H, m, Ar—H), 11.07 (1H, s, OH), 12.95 (1H, s, OH) MS(EI)m/z: 322, 320.

Synthesis of 7-Bromo-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (29)

To 5.5 g (F.W. 349.18, 15.75 mmol) of dimethoxylated compound (27) wasadded 80 mL of methanol and stirred. The obtained suspension was cooledto 0° C. Thereto 890 mg of sodium borohydride was dividedly addedseveral times. The reaction solution was returned to room temperatureand stirred for one hour. To the reaction solution was added dilutehydrochloric acid to stop thereaction, and methanol was distilled offunder reduced pressure. To the resulting reaction solution was addedethyl acetate to effect partition. The organic layer was washed withwater and then with a saturated sodium chloride aqueous solution, andsubsequently dried with anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure to obtain an oily substance, and 20mL of pyridine and 3.6 g of tosyl chloride were added to the oilysubstance and stirred at 90° C. overnight. The reaction solution waspartitioned with ethyl acetate and dilute hydrochloric acid. The organiclayer was washed with water and then with a saturated sodium chlorideaqueous solution, and subsequently dried with anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=5:1)(4.96 g, yield 95%). The oilysubstance thus obtained was dissolved in 50 mL of ethyl acetate and 150mg of palladium (IV) oxide added thereto to effect catalytic reductionat room temperature for one day. After completion of the reaction thereaction solution was filtered and concentrated and the residue waspurified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=10:1) (4.21 g, yield 84%; melting point 60.0-66.2°C.). To the obtained crystals 150 mg (F.W. 335.20, 0.45 mmol) was added2 g of pyridine hydrochloride and the resulting solution was stirred at200° C. under heating for two hours. After completion of the reaction,the reaction solution was partitioned with ethyl acetate and dilutehydrochloric acid. The organic layer was washed with water and then witha saturated sodium chloride aqueous solution, and subsequently driedwith anhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=1:1). Theproduct thus obtained was recrystallized from chloroform-hexane toobtain 80 mg (58%) of the title compound as pink plates.

Melting Point: 177.5-179.5° C. ¹H NMR (90 Mz, DMSO-d₆) δ: 2.7-2.9(2H, m,CH₂), 2.9-3.1 (2H, m, CH₂), 6.0-6.2 (2H, m, Ar—H), 7.1-7.4 (3H, m,Ar—H), 9.22 (1H, s, OH), 9.41 (1H, s, OH) MS(EI) m/z: 308, 306, 227.

Referential Example 6

Method of Preparing1-Chloro-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one (38)

Synthesis of Carboxylic Acid (31)

To a mixture of 9.32 g (F.W. 191.01, 48.8 mmol) of 2,6-dichlorobenzoicacid (30), 6.60 g (F.W. 154.165, 4.29 mmol) of 3,5-dimethoxyphenol (13),9.32 g (F.W. 138.21, 67.4 mmol) of potassium carbonate and 56 mL ofN-methyl-2-pyrrolidone was added benzene (40 mL), and the resultingsolution was dried by a Dean-Stark water separator (140-170° C.) forthree hours and then, 614 mg (F.W. 63.55, 9.67 mmol) of copper (powder)and 2.30 mg (F.W. 190.45, 12.1 mmol) of copper (I) iodide were addedthereto and the obtained solution was stirred at 140° C. for one hour.This reaction mixture was cooled by standing and ice water and ethylacetate were added thereto and then, the resulting solution was made pH2 with concentrated hydrochloric acid and filtered. The organic layerwas separated and then, thoroughly washed with water and subjected tosalting out with a saturated sodium chloride aqueous solution. Theresulting solution was dried with anhydrous magnesium sulfate andconcentrated. The residue (17 g) was purified by column chromatography(silica gel, water content of 6%; 340 g, ethyl acetate:hexane=1:2) toobtain 5.05 g (38%) of crystals (31).

Synthesis of Esterified Compound (32)

To a mixed solution of 2.5 g (F.W. 353.168, 8.10 mmol) of carboxylicacid (31) in 10 mL of dichloromethane and 10 mL of methanol was added anether solution of diazomethane until the yellow color disappeared. Thereaction solution was concentrated and purified by column chromatography(silica gel; 90 g, ethyl acetate:hexane=1:4) to obtain 2.507 g (98%) ofan esterified compound (32)(TLC; ethyl acetate:hexane=1:4).

Synthesis of Alcohol (33)

To a mixture of 250 mg (F.W. 37.83, 6.60 mmol) of lithium aluminumhydride and 10 mL of diethyl ether was added a solution of 2.51 g (F.W.322.744, 7.76 mmol) of esterified compound (32) in ether (5+3 mL)portionwise at 0° C. under stirring. After stirring at room temperaturefor three hours, a 90% methanol solution and a saturated ammoniumchloride aqueous solution were added to the resulting reaction solution.The organic layer was separated and washed with a saturated sodiumchloride aqueous solution three times. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was purified by column chromatography (silica gel; 150 g, ethylacetate:hexane-3:7) to obtain 1.53 g (64%) of alcohol (33). (TLC; ethylacetate:hexane=1:4).

Synthesis of Bromide (34)

By azeotropy with benzene, 2.24 g (F.W. 308.761, 7.28 mmol) of alcohol(33) was dried. A 5 mL of methylene chloride to which 0.254 mL (F.W.270.70, d=2.85, 2.67 mmol) of phosphorus tribromide had been added and5.6 mL of methylene chloride were added thereto at 0° C. and stirred atroom temperature for two hours. To the reaction mixture was added icewater and the resulting solution was extracted with ethyl acetate andthe extract was washed with water and then with a saturated sodiumchloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 2.58 g (99%) of bromide (34) as crystals.(TLC; ethyl acetate:hexane=1:4).

Synthesis of Nitrile Compound (35)

In 5 mL of dimethyl sulfoxide was dissolved 2.58 g (F.W. 357.631, 7.21mmol) of bromide (34). To this solution was added 530 mg (F.W. 49.01,10.82 mmol) of sodium cyanide and stirred at 800C for 30 minutes. Undercooling with ice water, to the reaction solution was added water andthen, the resulting solution was extracted with ethyl acetate threetimes. The extract was washed with water and then with a saturatedsodium chloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 1.95 g (89%) of nitrile compound (35).(TLC; ethyl acetate:hexane=1:4).

Synthesis of Phenylacetic Acid (36)

To 1.93 g (F.W. 303.745, 6.35 mmol) of nitrile compound (35) were added4.56 mL of ethanol and 4.56 mL [1.13 g (F.W. 40.00, 28.3 mmol) of sodiumhydroxide] of a 6N sodium hydroxide and stirred at 110° C. overnight. Tothe reaction solution was added ice and the resulting solution was madepH 2 with concentrated hydrochloric acid. The reaction solution thusobtained was extracted with ethyl acetate and the extract was washedwith water and then with a saturated sodium chloride aqueous solution.After drying with anhydrous magnesium sulfate, the solvent wascompletely removed under reduced pressure and the residue wascrystallized from benzene-hexane to obtain 1.36 g (66%) of phenylaceticacid (36). (TLC; ethyl acetate:hexane=1:2 or 1:1).

Synthesis of Cyclized Compound (37)

To 1.30 g (F.W. 332.74, 4.03 mmol) of carboxylic acid (36) was added 6mL of toluene to dissolve carboxylic acid (36) and then, polyphosphoricacid (10 mL of phosphoric acid and 7 g of phosphorus pentoxide havingbeen heated at 150° C.) was added thereto and the obtained solution wasconcentrated. This solution was stirred at 100° C. for 1.5 hours. To theresulting reaction solution was added ice water and the solution thusobtained was extracted with ethyl acetate and treated according to theconventional method to obtain a crude product. This crude product wasrecrystallized from hexane-methylene chloride to obtain 1.17 g (85%) ofcyclized compound (37). (TLC; ethyl acetate:hexane=1:2).

Synthesis of1-Chloro-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one (38)

To 150 mg (F.W. 304.729, 0.492 mmol) of dimethoxylated compound (37) and0.15 mL of benzene was added 2.0 g of pyridine hydrochloride and stirredat 195° C. for 1.5 hours with heating and then, ice water was slowlyadded thereto. The resulting solution was extracted with ethyl acetateand the extract was washed with 1N hydrochloric acid, water and asaturated sodium chloride aqueous solution in the order named. Afterdrying with anhydrous magnesium sulfate, the dried extract wasconcentrated. The residue was purified by silica gel columnchromatography (developing solvent; ethyl acetate:hexane=1:2).Furthermore, the product thus obtained was recrystallized fromdichloromethane-hexane to obtain 104 mg (77%) of the title compound.(TLC; ethyl acetate:hexane=1:2).

Referential Example 7

Method of Preparing of 9-Chloro-10,11-dihydrodibenz[b,f]oxepin-1,3-diol(40)

Reduction of Ketone of Ring B

In 20 mL of ethylene glycol was dissolved 475 mg (F.W. 304.729, 1.56mmol) of ring B-ketone compound (37) and 2.25 mL (F.W. 50.06. d=1.032,46.5 mmol) of hydrazine-monohydrate and 3.05 g (F.W. 56.11, 54.3 mmol)of potassium hydroxide were added thereto and stirred at 70° C. for 4.5hours. After raising the temperature up to 140° C., the reactionsolution was further stirred for two hours. Under cooling with ice, thereaction solution was neutralized by addition of 4N hydrochloric acid.The reaction solution thus neutralized was extracted with ethyl acetateand the extract was washed with water and then with a saturated sodiumchloride aqueous solution. After drying with anhydrous sodium sulfate,the solvent was removed under reduced pressure. The residue was purifiedby silica gel column chromatography (developing solvent; hexane:ethylacetate=19:1) to obtain 347 mg (F.W. 290.746, 1.19 mmol, 76%) of areduced compound (39).

Deprotection

To 347 mg (F.W. 290.746, 1.19 mmol) of dimethoxy compound (39) was added3.5 g of pyridine hydrochoride and stirred at 200° C. for two hours withheating and then, ice water was slowly added thereto. The reactionsolution was extracted with ethyl acetate and the extract was washedwith 1N hydrochloric acid, water and a saturated sodium chloride aqueoussolution in the order named. After drying with anhydrous sodium sulfate,the extract thus washed was concentrated. The residue was purified bysilica gel column chromatography (developing solvent; ethylacetate:hexane=3:1) and further recrystallized from chloroform-hexane toobtain 225 mg (F.W. 262.692, 0.86 mmol, 72%) of the title compound (40).

EXAMPLES

The present invention will now be explained in more detail based onExamples but the present invention is not limited to them or the likeand may be changed without departing from the scope of the presentinvention. The elution in the chromatography of Example was carried outunder observation by thin-layer chromatography (TLC) unless expresslystated otherwise. In the TLC observation, “60F₂₅₄” of Merck was used asthe TLC plate and as the developing solvent, a solvent which was used asthe eluting solvent in column chromatography was used. Further, an UVdetector was employed in detection. As the silica gel for the columnchromatography, “Silica Gel 60” (70 to 230 mesh) of Merck or“Microsphere Gel D75-60A” of Asahi Glass was used. The term “roomtemperature” means about 10° C. to about 35° C.

Example 1

Preparation of2-Methylthio-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one(Compound of Example 1)

Synthesis of Carboxylic Acid (42)

To a mixture of 60.8 g (F.W. 202.66, 0.30 mmol) of5-thiomethyl-2-chlorobenzoic acid (41), 21.0 g (F.W. 338.448, 0.15 mmol)of 3,5-dimethoxy disulfide (9), 21.0 g (F.W. 138.21, 0.15 mmol) ofpotassium carbonate and 300 mL of N-methyl-2-pyrrolidone was addedbenzene (100 mL×3), and the resulting mixture was subjected toazeotropic drying by a Dean-Stark water separator and then, heated at135° C. To this reaction solution were added 9.53 g (F.W. 63.55, 0.15mol) of copper (powder) and 28.57 g (F.W. 190.45, 0.15 mol) of copper(I) iodide and stirred at 135° C. for 5.5 hours. This reaction mixturewas cooled by standing and ice water and ethyl acetate were addedthereto and then, the resulting solution was made pH 2 with concentratedhydrochloric acid and filtered. The organic layer was separated andthen, thoroughly washed with water and subjected to salting out with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate and concentrating, the resulting crude carboxylic acidwas recrystallized from 2-butanone-isopropyl ether to obtain 65.08 g ofcarboxylic acid (42). Total yield: 65.08 g(65%)+11.03 g of mother liquor(purity 40%) (TLC; ethyl acetate:hexane=1:2 or 1:1).

MS(EI): 336, 318, 303, 244 NMR (CDCl₃): 2.48 (3H, s, CH₃), 3.78 (6H, s,CH₃×2), 6.50 (1H, d, J=2.2 Hz, Ar—H), 6.69 (1H, d, J=2.2 Hz, Ar—H), 6.91(1H, d, J=8.5 Hz, Ar—H), 7.22 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 7.97 (1H,d, J=2.2 Hz, Ar—H)

Synthesis of Alcohol (43)

To a solution of 50.45 g (F.W. 336.432, 150 mmol) of carboxylic acid(42) in 200 mL of tetrahydrofuran was added 6.24 g (F.W. 37.83, 165.0mmol) of sodium borohydride in small portions at room temperature andthen, 20.29 mL (F.W. 141.93, d=1.154, 165.0 mmol) of boron trifluoridediethyl etherate was added dropwise thereto. The resulting mixture wasstirred at room temperature for one hour. To the reaction solution wasslowly added ice water. The resulting solution was extracted with ethylacetate and washed with a saturated sodium chloride aqueous solutionthree times. After drying with magnesium sulfate, the solvent wasremoved under reduced pressure. The residue was recrystallized fromdiisopropyl ether to give 46.23 g of alcohol(43). These crystals wererecrystallized from ethyl acetate-hexane again to obtain 43.61 g (77%)of a product. (TLC; ethyl acetate:hexane=1:2).

MS(EI): 322, 303, 289, 273 NMR (CDCl₃): 2.51 (3H, s, CH₃), 3.71 (6H, s,CH₃×2), 4.74 (2H, d, J=6.3 Hz, CH₂), 6.26 (3H, s, Ar—H), 6.85 (1H, dd,J=8.5, 2.2 Hz, Ar—H), 7.40 (1H, d, J=2.2 Hz, Ar—H), 7.42 (1H, d, J=8.5Hz, Ar—H).

Synthesis of Bromide (44)

To a solution of 59.06 g(F.W. 322.449, 175.5 mmol) of alcohol (43) inmethylene chloride (127 mL) was added 6.4 mL (F.W. 118.97, d=1.631, 64.4mmol) of phosphorus tribromide at 0° C. and stirred at the sametemperature for 30 minutes. The reaction solution was further stirred atroom for 15 minutes. To the reaction mixture was added ice water and theresulting solution was extracted with ethyl acetate and washed withwater and then with a saturated sodium chloride aqueous solution. Afterdrying with anhydrous magnesium sulfate, the solvent was removed underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent; ethyl acetate:hexane=1:5) and then,recrystallized from ethyl acetate-hexane to obtain 57.74 g (82%) ofbromide (44). (TLC; ethyl acetate:hexane=1:4).

MS(EI): 386, 384 NMR (CDCl₃): 2.50 (3H, s, CH₃), 3.73 (6H, s, CH₃×2),4.64(2H, s, CH₂), 6.28 (1H, d, J=2.2 Hz, Ar—H), 6.33 (2H, d, J=2.2 Hz,Ar—H), 7.12 (1H, dd, J=8.2, 2.4 Hz, Ar—H), 7.33 (1H, d, J=8.2 Hz, Ar—H), 7.35(1H, d, J=2.4 Hz, Ar—H).

Synthesis of Nitrile Compound (45)

In 127 mL of dimethyl sulfoxide was dissolved 57.74 g (F.W. 385.346,149.8 mmol) of bromide (44). To this solution was added 11.02 g (F.W.49.01, 224.8 mmol) of sodium cyanide and stirred at 80° C. for 45minutes. Under cooling with ice water, to the reaction solution wasadded water and then, the obtained solution was extracted with ethylacetate three times. The extract was washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to obtain 34.83 g(70%) of nitrile compound (45). (TLC; ethyl acetate:hexane=1:4).

MS(EI): 331 NMR (CDCl₃): 2.53 (3H, s, CH₃), 3.72 (6H, s, CH₃), 3.85 (3H,s, CH₃), 6.20 (2H, d, J=2.5 Hz, Ar—H), 6.27 (1H, d, J=2.5 Hz, Ar—H),7.19 (1H, dd, J=8.5, 2.3 Hz, Ar—H), 7.44 (1H, d, J=2.3 Hz, Ar—H ), 7.45(1H, d, J=8.5 Hz, Ar—H).

Synthesis of Phenylacetic Acid (46)

To 30.07 g (F.W. 331.46, 90.8 mmol) of nitrile compound (45) were added75 mL of ethanol and 75 mL of a 6N sodium hydroxide aqueous solution[18.06 g (F.W. 40.00, 450 mmol) of sodium hydroxide] and stirred at 110°C. overnight. To the reaction solution was added ice and the resultingsolution was made pH 2 with concentrated hydrochloric acid. The reactionsolution thus obtained was extracted with ethyl acetate and the extractwas washed with water and then with a saturated sodium chloride aqueoussolution. After drying with anhydrous magnesium sulfate, the solvent wascompletely removed under reduced pressure and the residue wascrystallized from benzene-hexane to obtain 28.86 g (91%) of phenylaceticacid (46). (TLC; ethyl acetate:hexane=1:2 or 1:1).

MS(EI): 350, 273 NMR (CDCl₃): 2.49 (3H, s, CH₃), 3.70 (6H, s, CH₃), 3.84(1H, s, CH₂), 6.25 (3H, m, Ar—H), 7.15 (1H, dd, J=8.5, 2.3 Hz, Ar—H),7.21 (1H, d, J=2.3 Hz, Ar—H), 7.42 (1H, d, J=8.5 Hz, Ar—H), 12.91 (1H,s, OH).

Synthesis of Cyclized Compound (47)

To 27.89 g (F.W. 350.459, 32.0 mmol) of carboxylic acid (46) was added140 mL of methanesulfonic acid to dissolve carboxylic acid (46). Theresulting solution was stirred at 40° C. for one day. To the reactionsolution was added ice water to deposit a cyclized compound. Thedeposited cyclized compound was separated by filtration and extractedwith ethyl acetate and treated by the conventional method to obtain acrude product. This crude product was recrystallized fromhexane-methylene chloride to obtain 15.22 g (58%) of cyclized compound(47). (TLC; ethyl acetate:hexane=1:2).

MS(EI): 332, 347, 269 NMR (CDCl₃): 2.49 (3H, s, CH₃), 3.81 (3H, s, CH3),3.85 (3H, s, CH₃), 4.19 (1H, s, CH₂), 6.36 (1H, d, J=2.5 Hz, Ar—H), 6.66(1H, d, J=2.3 Hz, Ar—H), 7.04 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 7.22 (1H,d, J=2.2 Hz, Ar—H ), 7.46 (1H, d, J=8.5 Hz, Ar—H).

Synthesis of7-Methylthio-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one(Compound of Example 1)

To 27.88 g (F.W.332.44, 1.13 mmol) of dimethoxy compound (47) was added120 g of pyridine hydrochloride and stirred at 195° C. for 1.5 hourswith heating and then, ice water was slowly added thereto. The reactionsolution was extracted with ethyl acetate and the extract was washedwith 1N hydrochloric acid, water, a saturated sodium chloride aqueoussolution in the order named. After drying with anhydrous magnesiumsulfate, the extract thus obtained was concentrated. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:2). Furthermore, the residue was recrystallized fromisopropyl alcohol-2-butanone to obtain 19.40 g (64%) of the titlecompound.

Example 2

Preparation of 8-Methylthio-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol(Compound of Example 2)

In 50 mL of ethylene glycol was dissolved 665 mg (F.W. 332.43, 2.0 mmol)of cyclized compound (47) and 2.9 mL (F.W. 50.06, d=1.032, 60.0 mmol) ofhydrazine monohydrate and 4.04 g (F.W. 56.11, 72.0 mmol) of potassiumhydroxide were added thereto and stirred at 80° C. for 1.5 hours. Afterraising the temperature to 140° C., the reaction solution was furtherstirred for five hours. Under cooling with ice, the reaction solutionwas neutralized by addition of 1N hydrochloric acid. The reactionsolution thus neutralized was extracted with ethyl acetate and washedwith water and then with a saturated sodium chloride aqueous solution.After drying with anhydrous sodium sulfate, the solvent was completelyremoved under reduced pressure to obtain a crude product. The residuewas purified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=19:1) to obtain 238.5 mg (37.5%) of a reducedcompound (48).

To 238.5 mg (F.W. 318.45, 0.75 mmol) of reduced compound (48) was added3.0 g of pyridine hydrochloride and stirred at 200° C. under heating forsix hours and then, ice water was slowly added thereto, and theresulting solution was extracted with ethyl acetate and the extract waswashed with 1N hydrochloric acid, water and a saturated sodium chlorideaqueous solution in the order named. After drying with anhydrous sodiumsulfate, the obtained solution was concentrated. The residue waspurified by silica gel column chromatography (developingsolvent;hexane:ethyl acetate=19:1) and further recrystallized fromhexane-ethyl acetate to obtain 132.7 mg (61%) of the title compound.

Example 3

Preparation of11-Diethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one(Compound of Example 3)

To a suspension of 1.92 g (60% content, F.W. 24.00, 48.0 mmol) of sodiumhydride and 50 mL of tetrahydrofuran was added dropwise a solution of5.72 g (F.W. 286.34, 20.0 mmol) of compound (49) dissolved in 200 mL oftetrahydrofuran. The resulting suspension was stirred at roomtemperature for 30 minutes and then, 3.84 mL (F.W. 155.97, d=1.94, 48.0mmol) of ethyl iodide was added thereto and further stirred at roomtemperature for two days. Under cooling with ice, ammonium chloride wasadded to the reaction solution and the tetrahydrofuran was completelyremoved under reduced pressure and then, the residue was partitionedwith ethyl acetate and water and washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydroussodium sulfate, the solvent was completely removed under reducedpressure to obtain 9.34 g of a crude product. The residue was purifiedby silica gel column chromatography (developing solvent; hexane:ethylacetate=9:1 to 3:1) to obtain 3.62 g of a mixture of compound (50) withcompound (51) and 2.62 g (F.W. 342.45, 7.65 mmol, 38.2%) of compound(52). The by-product of compound (52) was subjected to acid treatmentwith ethanol-concentrated hydrochloric acid to be converted to compound(51). With compound (51) the above described reaction was repeated to beled to compound (50).

The crude products (50) were combined and purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=9:1 to 5:1) toobtain 3.73 g (F.W. 342.45, 10.89 mmol, 54.5%) of compound (50).Demethylation reaction was carried out according to the method ofExample 1 to obtain the title compound.

Example 4

Preparation of11-Ethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 4)

To a suspension of potassium tert-butoxide (12.3 g, 110 mmol) and 500 mLof tetrahydrofuran was added dropwise a solution of 30 g (F.W. 286.34,105 mmol) of compound (49) in 500 mL of tetrahydrofuran at 0° C. Thissuspension was stirred at room temperature for two hours and then,cooled to 0° C., and 16.8 mL (F.W. 155.97, d=1.94, 210 mmol) of ethyliodide was added thereto and stirred at room temperature for 20 hours.Under cooling with ice, hydrochloric acid was added to the reactionsolution, and tetrahydrofuran was completely removed under reducedpressure and then, the residue was partitioned with ethyl acetate andwater and the organic layer was washed with water and then with asaturated sodium chloride aqueous solution and dried with anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=4:1) and then, recrystallized frommethanol to obtain 18.7 g (yield 57%) of compound (51). Thedemethylation reaction of compound (51) was carried out according to themethod of Example 1 to obtain 14.8 g of the title compound.

Example 5

Preparation of3-(2-Thiophene)-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one(Compound of Example 5)

To 3-bromo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one (27) (500mg, 1.4 mmol), 2-(tributylstannyl)thiophene (0.9 mL, 2.8 mmol) andtetrakis(triphenylphosphine) palladium (82.5 mg, 0.07 mmol) was added 5mL of hexamethylphosphoric triamide and stirred at 100° C. for one hour.After completion of the reaction, the reaction solution was partitionedwith diethyl ether and water, and the organic layer was washed withwater and then with a saturated sodium chloride aqueous solution anddried with anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (developing solvent; hexane:ethyl acetate=1:1) toobtain 538 mg (yield 89%) of3-(2-thiophene)-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one.Demethylation reaction was carried out according to the method ofExample 1 to obtain the title compound.

Example 6

Preparation of3-Phenyl-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one (Compoundof Example 6)

To 3-iodo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one (52) (403mg, 1.0 mmol), phenyl boronic acid (186 mg, 1.5 mmol), a 2M potassiumcarbonate aqueous solution (0.6 mL, 1.2 mmol) andtetrakis(triphenylphosphine) palladium (118 mg, 0.10 mmol) was added 5mL of toluene and stirred at 125° C. for 19 hours. After completion ofthe reaction, the reaction solution was neutralized with dilutehydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water and then with a saturated sodium chloride aqueoussolution and dried with anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent; hexane:ethyl acetate=2:1)to obtain 108 mg (yield 31%) of3-phenyl-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one.Demethylation reaction was carried out according to the method ofExample 1 to obtain the title compound.

Example 7

Preparation of 7-Phenyl-10,11-dihydrodibenz[b,f]oxepin-1,3-diol(Compound of Example 7)

To 1,3-dimethoxy-7-bromo-10,11-dihydrodibenz[b,f]oxepin (53) (970 mg,2.9 mmol) obtained by reducing the 10-position of the carbonyl group ofthe previous compound (27), phenylboronic acid (380 mg, 3.1 mmol),potassium carbonate (1.98 mg, 14.3 mmol), palladium acetate (20 mg, 0.09mmol) and tetra-n-butylammonium bromide (920 mg, 2.9 mmol) was added 5mL of water and stirred at 70° C. for one hour. After completion of thereaction, the reaction solution was neutralized with dilute hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withwater and then with a saturated sodium chloride aqueous solution anddried with anhydrous magnesium sulfate, and the solvent distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (developing solvent;hexane:ethyl acetate=10:1) toquantitatively obtain 1.05 g of1,3-dimethoxy-7-phenyl-10,11-dihydrodibenz[b,f]oxepin. Demethylationreaction was carried out according to the method of Example 1 to obtainthe title compound.

Example 8

Preparation of3-Iodo-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 8)

Synthesis of Carboxylic Acid (55)

A mixture of 14.1 g (F.W. 282.46, 50.0 mmol) of 2-chloro-3-iodobenzoicacid (54), 8.46 g (F.W. 338.44, 25.0 mmol) of disulfide (9), 1.58 g(F.W. 63.55, 25.0 mmol) of copper (powder), 4.76 g (F.W. 190.45, 25.0mmol) of copper (I) iodide, 12.4 g (F.W. 138.21, 90.0 mmol) of potassiumcarbonate and 100 mL of N-methyl-2-pyrrolidone was stirred at 120° C.for 1.5 hours. This reaction solution was cooled by standing, and madepH 2 with 4N hydrochloric acid. The resulting solution was extractedwith ethyl acetate and washed with water and a saturated sodium chlorideaqueous solution in the order named. After drying with anhydrous sodiumsulfate, the solvent was removed under reduced pressure, and theresulting crude carboxylic acid was recrystallized from ethyl acetate toobtain 4.21 g (F.W. 416.23, 10.1 mmol) of carboxylic acid (55). Thefiltrate after recrystallization was further crystallized (from ethylacetate) to obtain 3.45 g (F.W. 416.23, 8.3 mmol) of carboxylic acid(55). The yield was 36.8%.

Synthesis of Alcohol (56)

To a solution of 7.66 g (F.W. 416.23, 18.4 mmol) of carboxylic acid (55)in 20 mL of tetrahydrofuran was added 722 mg of sodium borohydride andthen, 2.74 mL of boron trifluoride diethyl etherate was added dropwisethereto. The resulting mixture was stirred at room temperature for 45minutes. Ice water was slowly added to this reaction solution. Thereaction solution thus obtained was extracted with ethyl acetate andwashed with a saturated sodium chloride aqueous solution. After dryingwith anhydrous magnesium sulfate, the solvent was removed under reducedpressure. The resulting crude product was purified by columnchromatography (developing solvent; hexane:ethyl acetate=4:1) toquantitatively obtain 7.59 g (F.W. 402.25) of alcohol (56).

Synthesis of Bromide Compound (57)

To a solution of 7.49 g (F.W. 402.25) of crude alcohol (56) in 20 mL ofmethylene chloride was added 0.62 mL of phosphorus tribromide at 0° C.and stirred at room temperature for 30 minutes. To this reactionsolution was added slowly ice water. The reaction solution was furtherstirred at room temperature for 30 minutes and then, extracted withmethylene chloride and the extract was washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. As aresult, a crude product was obtained. This crude product was purified bysilica gel column chromatography (developing solvent; hexane:ethylacetate=4:1) to obtain 5.14 g (F.W. 465.14, 11.05 mmol) of bromide (57).The yield was 61.4% in two steps.

Synthesis of Nitrile Compound (58)

In 20 mL of dimethyl sulfoxide was dissolved 5.00 g (F.W. 465.14, 10.75mmol) of bromide (57). To this solution was added 630 mg of sodiumcyanide and stirred at 80° C. for one hour. Under cooling with ice, tothe resulting solution was added water and then, the obtained solutionwas extracted with ethyl acetate, and the extract was washed with waterand a saturated sodium chloride aqueous solution in the order named.After drying with anhydrous magnesium sulfate, the solvent was removedunder reduced pressure and the crude product thus obtained was purifiedby silica gel column chromatography (developing solvent; hexane:ethylacetate=3:1) to obtain 2.30 g (F.W. 411.26, 5.59 mmol) of nitrilecompound (58) and 2.06 g (F.W. 411.26) of crude nitrile compound (58).

Synthesis of Carboxylic Acid (59)

To 30 ml of ethanol 2.27 g (F.W. 411.26, 5.5 mmol) of nirile compound(58) was added and completely dissolved by raising the temperature to110° C. To this solution was added 2.35 mL of a 1N sodium hydroxideaqueous solution. The resulting solution was further stirred at 110° C.overnight. To the reaction solution was added ice and the obtainedsolution was neutralized with 1N hydrochloric acid. The resultingsolution was extracted with ethyl acetate and the extract was washedwith water and then with a saturated sodium chloride aqueous solution.After drying with anhydrous magnesium sulfate, the solvent wascompletely removed under reduced pressure to obtain 2.36 g (F.W. 430.26)of crude carboxylic acid (59).

Synthesis of Cyclized Compound (60)

To 4.40 g (F.W. 430.26 mmol) of crude carboxylic acid (59) was added 60mL of methanesulfonic acid to dissolve crude carboxylic acid (59). Theresulting solution was stirred at room temperature overnight. To thereaction solution was added water under cooling with ice and then, theresulting solution was extracted with ethyl acetate and the extract waswashed with water and then with a saturated sodium chloride aqueoussolution. After drying with anhydrous magnesium sulfate, the solvent wascompletely removed to obtain a crude product which was then purified bysilica gel column chromatography (developing solvent; hexane:ethylacetate=4:1). Furthermore, recrystallization of the product thusobtained was repeated from hexane and methylene chloride and from hexaneand ethyl acetate to obtain 1.82 g (F.W. 412.24, 4.4 mmol) of cyclizedcompound (60). The yield was 41.1% in three steps.

Synthesis of3-Iodo-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 8)

To 412.2 mg (F.W. 412.24, 1.0 mmol) was added 2.0 g of pyridinehydrochloride and the temperature was raised up to 200° C. The resultingsolution was stirred at 200° C. for two hours and then, ice water wasslowly added thereto. The reaction solution thus obtained was extractedwith ethyl acetate to which a small amount of tetrahydrofuran had beenadded and the extract was washed with 1N hydrochloric acid, water and asaturated sodium chloride aqueous solution in the order named. Afterdrying with anhydrous magnesium sulfate, the solvent was completelyremoved under reduced pressure to obtain 289.1 mg of a crude product.This crude product was purified by silica gel column chromatography(developing solvent; hexane:ethyl acetate=9:1 to 4:1). Furthermore, theproduct thus obtained was recrystallized from chloroform to obtain 150.1mg (F.W. 384.19, 39.1 mmol) of the title compound. The yield was 39.1%.

Example 9

Preparation of3-Bromo-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 9)

Synthesis of Carboxylic Acid (61)

A mixed solution of 58.87 mg (F.W. 235.47, 0.25 mmol) of3-bromo-2-chlorobenzoic acid (3), 42.31 mg (F.W. 338.44, 0.10 mmol) ofdisulfide (80%) (9), 7.94 mg (F.W. 63.55, 0.125 mmol) of copper(powder), 23.81 mg (F.W. 190.45, 0.125 mmol) of copper (I) iodide, 41.46mg (F.W. 138.21, 0.30 mmol) of potassium carbonate and 3 mL ofN-methyl-2-pyrrolidone was stirred at 150° C. for 2.5 hours. Thisreaction solution was cooled by standing, and made pH 2 with 1Nhydrochloric acid. The resulting solution was extracted with ethylacetate and washed with water and a saturated sodium chloride aqueoussolution in the order named. After drying with anhydrous sodium sulfate,the solvent was removed under reduced pressure to give crude carboxylicacid (61) (F.W. 369.23). The yield was 64.5% by HPLC.

The procedure after the synthesis of carboxylic acid (61) was carriedout according to the method of Example 8 to obtain the title compound.

Example 10

Preparation of 8-Propionyl-10,11-dihydrodibenz[b,f]oxepin-1,3-diol(Compound of Example 10)

To a suspension of aluminum chloride (1 g, 7.5 mmol) in anhydrousmethylene chloride (3 mL) was added propionyl chloride (668 μL, 7.7mmol) and stirred at room temperature for one hour. This solution wasadded dropwise to a solution of 10,11-dihydrodibenz[b,f]oxepin-1,3-dioldiacetate (62) (300 mg, 0.96 mmol) in methylene chloride (5 mL) at 0° C.and stirred at room temperature for one hour. To the reaction solutionwas added dropwise methanol (10 mL) at 0° C. and a 20% sodium hydroxideaqueous solution (3 mL) was added thereto and stirred at roomtemperature for 30 minutes. After completion of the reaction, thereaction solution was poured into hydrochloric acid-ice water andextracted with ethyl acetate, and the organic layer was washed withwater and then with a saturated sodium chloride aqueous solution anddried with anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=2:1), andrecrystallization was carried out from ethyl acetate and hexane toobtain 190 mg (yield 70%) of skin-colored needles of the title compound.

Example 11

Preparation of8-(1-Hydroxyiminoethyl)-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol(Compound of Example 11)

In ethanol, 180 mg of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol(63) was dissolved, and an aqueous solution of 49 mg of hydroxylaminehydrochloride and 100 mg of sodium acetate dissolved in 1 mL of waterwas added thereto. The mixed solution was stirred at 120° C. for 3hours, concentrated under reduced pressure and then, extracted withethyl acetate. The organic layer was washed with water and a saturatedsodium chloride solution and then, dried with anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=1:1). Upon recrystallization fromchloroform-hexane, 120 mg of skin-colored amorphous title compound wasobtained (yield 63%).

Melting Point: 215.4 to 217.5° C.

Example 12

Preparation of 8-Hexyl-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (Compoundof Example 12)

In a pressure reaction vessel, 200 mg of2-bromo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one (64), 32 mgof a palladium complex, 34 mg of triphenylphosphine and further 11.8 mgof copper iodide were charged and 3 mL of acetonitrile (dehydrated) wasadded thereto and stirred. To this solutionO,N-bis(trimethylsilyl)acetamide (hereinafter referred to as “BSA”) wasadded at room temperature and stirred for 5 minutes to effectsilylation. After silylation, 110 μL of 1-hexyne and 250 μL ofN,N-diisopropylethylamine were added and the vessel was heat sealed, andstirred at 120° C. under heating for 17 hours. After completion of thereaction, the reaction solution was partitioned with ethyl acetate anddilute hydrochloric acid. The organic layer was washed with water and asaturated sodium chloride solution and then, dried with anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(developing solvent; hexane:ethyl acetate=3:1). To the obtained oilysubstance was added 5 mL of ethyl acetate to dissolve the oily substanceand 20 mg of palladium-carbon was added thereto to effect hydrogenationovernight. After completion of the reaction, the reaction solution wasfiltered, concentrated and the residue as purified by silica gel columnchromatography (developing sovent; hexane:ethyl acetate=7:1). Uponrecrystallization from chloroform-hexane, 49.3 mg of colorless plates ofthe title compound was obtained (yield 24.3%).

Various compounds of the present invention were synthesized in the samemanner as in each of the above described Examples. The structures of atotal of 178 compounds synthesized including the compounds synthesizedin Examples 1 to 12, and the compounds of Examples used in the followingExperimental Examples are collectively shown below. These compounds canbe prepared by combinations of {circle around (1)}: Ullmann reaction;{circle around (2)}-1: Friedel-Crafts reaction or {circle around (2)}-2:photoreaction; {circle around (3)}: carbon atom increasing reaction;{circle around (4)}: conversion reaction of a halogens to anotherfunctional group; {circle around (5)}: introduction reaction of an alkylgroup or an alkylcarbonyl group; {circle around (6)}: conversionreaction at 10-position; and {circle around (7)}: reaction ofDeprotection according to the same methods as the preparation methods ofReferential Examples and Examples, and the preparation steps of eachcompound will be explained in Table 1.

Further, the data of the properties of these compounds are listed inTable 2 to Table 18.

TABLE 1 Example Nos. Preparation Steps Examples 13 to 23 {circle around(1)}→{circle around (2)}-1→{circle around (3)}→{circle around (7)}Examples 24 to 36 {circle around (1)}→{circle around (2)}-1→{circlearound (3)}→{circle around (6)}→{circle around (7)} Examples 37 to 46{circle around (1)}→{circle around (2)}-1→{circle around (3)}→{circlearound (5)}→{circle around (7)} Examples 47 to 101 {circle around(1)}→{circle around (2)}-1→{circle around (3)}→{circle around(4)}→{circle around (7)} Examples 102 to 127 {circle around (1)}→{circlearound (2)}-1→{circle around (3)}→{circle around (4)}→{circle around(6)}→{circle around (7)} Examples 128 to 151 {circle around (1)}→{circlearound (2)}-1→{circle around (3)}→{circle around (5)}→{circle around(6)}→{circle around (7)} Example 4, Example 37, {circle around(1)}→{circle around (2)}-2→{circle around (5)}→{circle around (7)}Example 152 Examples 153 to 163, {circle around (1)}→{circle around(2)}-1→{circle around (3)}→{circle around (4)}→{circle around(5)}→{circle around (7)} Examples 169 to 179 Example 1

Example 2

Example 3

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Example 61

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Comparative example

TABLE 2 Example melting point NMR Appear- No (centi degree) NMR solventIR ance Mass UV 1 189.4-191.9 2.47(3 H, s, CH3) · 4.03(2 H, s, CH2) ·DMSO-d6 3213- 332-285 λ max nm (ε) · 243 5.86(1 H, s, OH) · 6.15(1 H, d,J = 1611 (23100) · 278 2.5 Hz, Ar—H) · (27600) · 345.6 6.35(1 H, d, J =2.5 Hz, Ar—H) · (7900) · 7.15(1 H, s, Ar—H) · 7.20(2 H, d, J = 7.8 HzAr—H) · 12.96(1 H, s, OH) 2 161.6-163.9 2.97-3.00(2 H, m, CH2) · 3.27-DMSO-d6 3463- ε max 20209 (λ 3.30(2 H, m, CH2) · 3368- max 283.6 nm) · ε6.28(1 H, d, J = 2 Hz, Ar—H) · 1606 max 17842 (λ max 6.33(1 H, d, J = 2Hz, Ar—H) 259.6 nm) · 7.08(1 H, dd, J = 8.2 Hz, Ar—H) · 7.23(1 H, sAr—H) · 7.40(1 H, d, J = 8 Hz, Ar—H) · 7.62(1 H, s, Ar—H) · 9.28(1 H,brs, OH) · 9.49(1 H, brs, OH) 3 238.0-244.1 0.74(6 H, t, J = 7 Hz, CH3)· DMSO-d6 3467- needle 314 ε max 15545 (λ max 2.08(1 H, q, J = 7 Hz,CH2) 3267- crystal (M+, base) 260.8 nm) · ε max 2.11(1 H, q, J = 7 Hz,CH2) 2973- 20821 (λ max 2.36(1 H, q, J = 7 Hz, CH2) 2963- 244 nm) 2.49(1H, q, J = 7 Hz, CH2) · 2957- 6.83(1 H, s, Ar—H) 2934- 6.90(1 H, s, Ar—H)· 7.27(1 H, 2875- t, J = 7 Hz, Ar—H) · 1646- 7.44(1 H, t, J = 7 Hz,Ar—H) · 1596- 7.53(1 H, d, J = 7 Hz, Ar—H) 1508- 7.64(1 H, d, J = 7 Hz,Ar—H) · 1451- 9.68(2H 4 237.8- 0.90(3 H, t, J = 7.2 Hz, CH3) · DMSO-d63503- pinkish- 286(M+, ε max 6018 (λ 239.4 1.91-1.99(1 H, m, J = 3281-white Base)-271- max 338.4 nm) · ε (decom- 7.7 Hz, CH2) · 2.35- 2970-needle 257-229 max 22356 ( λ max position) 2.68(1 H, m, J = 7.7 Hz, CH2)· 1644- crystal 257.2 nm) · ε max 4.61(1 H, t, J = 7.1 Hz, CH) · 1596-23553 (λ max 6.96(1 H, s, Ar—H) ·  784 243.2 nm) 7.23 (1 H, t, J = 7.6Hz, Ar—H) · 7.35(1 H, d, J = 7.6 Hz, Ar—H) · 7.47(1 H, t, J = 7.7 Hz,Ar—H) · 7.49(1 H, s, Ar—H) · 7.70(1 H,d, J = 7.6 Hz, Ar—H) · 5227.6-228.1 4.18(2 H, s, CH2) · 6.16(1 H, d, J = DMSO-d6 3340- pale324(M+, Base) ε max 28742.1 (λ 2.4 Hz Ar—H) · 1633- yellow max 281.0 nm)· 6.50(1 H, d, J = 2.4 Hz, Ar—H) · 1610- needle 7.20(1 H, t, J = 4.3 Hz,Ar—H) ·  704- crystal 7.51-7.71(5 H, m, Ar—H) · 11.11(1 H, brs, OH) ·13.07(1 H, s, OH). 6 182.7-1844 4.21(2 H, s, CH2) · 6.16(1 H, d, J =DMSO-d6 3339- pale mud 318(M+, Base) ε max 7353 (λ 2.4 Hz, Ar—H) · 1614-yellow max 321.6 nm) · ε 6.5 (1H, d, J = 2.5 Hz, Ar—H) · 1586 needle max15358 (λ max 7.43(8 H, m, Ar—H) · crystal 286.2 nm) · ε max 11.10(1 H,brs, OH) · 13.08(1 H, 5, OH) 21057 (λ max 256.8 nm) 7 179.6-180.42.85-2.86(2 H, m, CH2) · 3.09- 3440- pale pink 304(M+, Base) λ max nm(ε) · 3.12(2 H, m, CH2) · 3368- plate crystal 207.6 (64200) · 247.86.18(1 H, d, J = 2.4 Hz, Ar—H) · 2923- (sh 24300) 6.19(1 H, d, J = 2.4Hz, Ar—H) · 2854- 7.35-7.53(6 H, m, Ar—H) · 1624- 7.70- 7.72(2 H, m,Ar—H) · 1610- 9.25(1 H, br, OH) · 9.44(1 H, br, OH) · 1509- 1457 8 >2504.36(2 H, s, CH2) · 6.26(1 H, d,J = DMSO-d6 3330- 384 ε max 8579.4 (λ(decom- 2 Hz, Ar—H) · 1618 (M+, base)- max 343.0 nm) · ε position)6.70(1 H, d, J = 2 Hz, Ar—H) · 351 (M+− max 12476.8 (λ max 7.37(1 H, d,J = 8 Hz, Ar—H) 33)-257 301.2 nm) · ε max · 7.84(1 H, dd, J = 8,1 Hz,(M+− 127) 31556.5 (λ max Ar—H) · 8.08(1 H, d, J = 1 Hz, 240.4 nm) · εmax Ar—H) · 11.10(1 H, brs, OH) · 49370 (λ max 13.48(1 H, s, OH) 203.0nm) 9 >200 4.31 (2 H,s, CH2) · 6.19(1 H, d, J = DMSO-d6 3338- white338(M+, ε max 7008 (λ subli- 2.3 Hz, Res-H) · 1599 needle Base)-336 ·max 340.0 nm) mation 6.63(1 H, d, J = 2.3 Hz, Res-H)- crystal 305-303- εmax 10843 (λ max and 7.46(1 H, d, J = 8 Hz, Ar—H) · 257- 301.6 nm)decom- 7.61(1 H, dd, J = 8.2 Hz, Ar—H) · ε max 9218 (λ position) 7.86(1H, d, J = 2, Ar—H) max 278.4 nm) · 11(1 H, brs, OH) · ε max 21932 (λ max13.40(1 H, s, OH) 238.8 nm) 10 159.0-160.3 1.05(3 H, t, J = 7 Hz, CH3) ·DMSO-d6 3361- pinkish 284(M+)- ε max 12965 (λ max 2.79(2 H, m, CH2) ·2.98(2 H, q, 3197- white 269- 260.8 nm) · J = 7 Hz, CH2) · 3.06(2 H, m,CH2) · 2944- needle 255(Base) ε max 12364(λ 6.07(1 H, d, J = 2.5 Hz,Ar—H) · 1660- crystal max 6.11(1 H, d, J = 2.5 Hz, Ar—H) · 1621- 245.6nm) · 7.18(1 H, d, J = 8 Hz, Ar—H) · 1598 ε max 51685(ν 7.78(1 H, dd, J= 2.8 Hz, Ar—H) · max 207.2 nm) 7.83(1 H, d, J = 2 Hz, Ar—H) · 9.26(1 H,br, OH) · 9.41(1 H, br, OH) 11 215.4-217.5 2.11(3 H, s, CH3) · 2.96(2 H,m, CH2) · DMSO-d6 3361- pinkish 301(M+, ε max 11366(λ max 3.23(2 H, m,CH2) · 6.23(1 H, d, J = 2938- white Base)-284 291.6 nm) · 2.4 Hz, Ar—H)· 6.28(1 H, d, J = 1607 amorphous ε max 10157(λ 2.4 Hz, Ar—H) · 7.39(2H, m, Ar—H) · max 7.51(1 H, m, Ar—H) · 273.2 nm) · 9.20(1 H, brs, OH) ·ε max 43942(λ 9.43(1 H, brs, OH) · max 211.6 nm) 11.20(1 H, brs, OH)

TABLE 3 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 12 109.5-111.2 0.820(3 H, t, J = 6.4 Hz, −CH3) ·DMSO-d6 3316- colorless ε max 6755 (λ max 1.23-1.26(6 H, m, CH2 * 3) ·2959- plate crystal 327.6 nm) · 1.507(2 H, t, J = 7.0 Hz, CH2) · 2924- emax 6396( λ max 2.521(2 H, t, J = 7.5 Hz, CH2) · 2856- 312.8 nm) ·4.040(2 H, s, CH2) · 6.060(1 H, d, J = 1636- ε max 13808 (λ max 2.3 Hz,Ar—H) · 6.333(1 H, d, J = 1593- 287.2 nm) · e max 2.3 Hz, Ar—H) ·7.089(1 H, dd, 1497- 4863 (λ max 255.6 nm) J = 8.0,1.3 Hz, Ar—H) ·7.16-1445 7.21(2 H, m, Ar—H) · 10.970(1 H, s, Ph—OH) · 12.997(1 H, s, Ph—OH)13 236.4-237.3 4.34(2 H, s, CH2) · 6.17(1 H, d, J = DMSO-d6 3339- paleyellow 336 λ max nm (ε) · 2.3 Hz, Res-H) · 6.62(1 H, d, J = 1618- needle(M+, base)- 206.4 (46400) · 38.5 2.3 Hz, Res-H) · 7.47(1 H, d, J = 1602crystal 303 (M+− (27700) · 272.4 8.3 Hz, Ar—H) · 7.59(1 H, d, J =33)-257 (13900) · 300.4 8.3 Ar—H) · 7.77(1 H, s Ar—H) · (M+− 79) (12600)· 340.0 (8800) 10.99(1 H, s, OH) · 13.37(1 H, s, OH) 14 187.5 3.90(3 H,s, CH3) · 4.46(2 H, m, CH2) · DMSO-d6 3448- white needle 352 λ max nm(ε) · (subli- 6.51(1 H, d, J = 2 Hz, Ar—H) · 1612- crystal (M++ 2.base)-2064 (44800) · 239.2 mation) 6.85(1 H,d,J = 2 Hz, Ar—H) 1576 350 (M+)-(25900) · 2707 · 7.58(1 H,d, J = 8 Hz, Ar—H) · 317 (M+− (14100) · 298.87.69(1 H, d, J = 8 Hz, Ar—H) · 33)-271 (11300) · 340.0 (6200) 7.89(1 H,s, Ar—H) · (M+− 79) 13.50(1 H, s, Ph—OH) ·· 15 217.9-221.6 4.43(2 H, s,CH2) · 6.26(1 H, d, J = DMSO-d6 3338- needle 292 λ max nm (ε) · 2 Hz,Ar—H) · 6.71(1 H, d, J = 3089- crystal (M+, base)- 203.6 (53600) · 269.62 Hz, Ar—H) · 7.43(1 H, dd, J = 1602 white 259 (M+− (14900) · 300.8 8.2Hz, Ar—H) · 33)- (13100) · 340.0 7.73(1 H, d, J = 2 Hz, Ar—H) · (9100) ·7.75(1 H,d, J = 8 Hz, Ar—H) · 11.09(1 H, brs, OH) · 13.46(1 H, s, OH) ·16 4.12(2 H, s, CH2) · 6.26(1 H, d, J = DMSO-d6 3368- λ max nm (ε) · 2Hz, Ar—H) · 3227- 287.6 (7500) · 326.4 6.71(1 H, d, J = 2 Hz, Ar—H) ·1634- (5500) · 7.43-7.75(3 H, d, J = 8 Hz, 1615- Ar—H) · 1 1.09(1 H,brs, OH) · 1498 12.94(1 H, s, OH) 17 >200 4.60(2 H, s, CH2) · 6.27(1 H,d, J = DMSO-d6 3362- ε max 8119 (λ max (decom- 2 Hz, Ar—H) · 6.72(1 H,d, J = 1617- 340.0 nm) · ε max position) 2 Hz, Ar—H) · 7.36(1 H, t, J =1595 12239 (λ max 8 Hz, Ar—H) · 7.64(1 H, d, J = 299.2 nm) · ε max 8 Hz,Ar—H) · 7.73(1 H, d, J = 23541 (λ max 8 Hz, Ar—H) · 11.11(1 H, brs, OH)· 240.8 nm) · ε max 13.42(1 H, s, OH) · 47654 (λ max 205.2 nm) 18245.3-246.6 2.47(3 H, s, CH3) · 4.03(2 H, s, CH2) · DMSO-d6 3168- needle320 (M+) λ max nm (ε) · 5.86(1 H, s, OH) · 6.15(1 H, d, J = 1610-crystal 203.6 (59600) · 286.8 2.5 Hz, Ar—H) · 6.35(1 H, d, J = 1578(18800) · 340.0 2.5 Hz, Ar—H) · 7.1 5(1 H,s Ar—H) · (13600) · 7.20(2 H,d, J = 7.8 Hz .Ar—H) · 12.96(1 H, s, OH) 19 182.3-184.4 2.48(3 H, s,CH3) · 4.27(2 H,s, CH2) · DMSO-d6 3333- needle 304(M+, λ max nm (ε) ·6.18(1 H, d, J = 2.4 Hz, Ar—H) · 1594 crystal Base)-271- 245.2 (23900) ·258.4 6.63(1 H, d, J = 2.3 Hz, Ar—H) · 257- (24100) · 298.4 7.30(1 H,d,J = 8.0 Hz, Ar—H) · (12400) · 340.0 7.42(1 H, d, J = 8.0 Hz, Ar—H)(9400) 7.51(1 H,s, Ar—H) · 10.9(1 H, br, OH) · 13.45(1 H, s, OH) 20 >2504.23 (2 H, s, CH2) · 6.97 (1 H, s, DMSO-d6 3453- pale brown 336(M+, εmax 15804 (λ max Ar—H) · 7.43(1 H, d, J = 3261- needle Base)-336 259.6nm) · ε max 8.1 Hz, Ar—H) · 1647- crystal 21547 (λ max 7.51 (1 H, s,Ar—H) · 1602- 240.4 nm) · ε max 7.59(1 H, dd, J = 8.1-1.8 Hz, 1589-34053 (λ max Ar—H) · 7.88(1 H, d, J = 1.6 Hz, 1512- 206.0 nm) Ar—H) · (2H, brs, OH) 1465 21 2.44(3 H, s, CH3) · 4.16(2 H, s, CH2) · DMSO-d63542- 304(M+)-257 λ max nm (ε) · 6.96(1 H, Ar—H) · 3344- (M+− SMe) 205.6(28400) · 249 6 7.25(1 H, m, Ar—H) · 1638- (23400) · 264.4 7.36(1 H, d,J = 8 Hz, Ar—H) · 1591- (25900) · 282.4 7.48(2 H, 8.Ar—H) 1506 (25200) ·337.6 (4900) 22 285.7 4.23(2 H,s, CH2) · DMSO-d6 3452- plate crystal33B(M+, λ max nm (ε) · (decom- 6.95(1 H, s, Ar—H) · 3246- Base)-336-246.8 (28400) · 283.3 position) 7.41(1 H, dd, J = 8.2 Hz, Ar—H) 1652-305-303- (15300) · 337.6 7.48(1 H, s, Ar—H) · 7.58(1 H, d, 1604 257-(6300) J = 8 Hz, Ar—H) · 7.70(1 H, d, J = 2 Hz, Ar—H) · (2 H, brs, OH)23 232.0-236.9 2.45(3 H, s, CH3) · DMSO-d6 3457- needle 304(M+)- λ maxnm (ε)- 4.20(1 H, s, CH2) · 3239- crystal 257(M+− 203.6 (36000) · 248.06.94(1 H, s, Ar—H) · 1647- SMe) (29300) · 260.4 7.10(1 H, dd, J = 1603-(29700) · 335.6 7.2.1 Hz, Ar—H) · (6800) 7.32(1 H, d, J = 1.0 Hz, Ar—H)· 7.48(1 H, s, Ar—H) ·7.55(1 H, d, J = 8.2 Hz, Ar—H) ·

TABLE 4 Example melting point NMR Appear- No (centi degree) NMR solventIR ance Mass UV 24 208.0-213.7 4.20(2 H, s, CH2) · 6.06(1 H, d, J =DMSO-d6 3390- colorless 257(M+, ε max 13691 3 Hz, Ar—H) · 6.29(1 H, d, J= 3339- needle Base)-211 (λ max 3 Hz, Ar—H) · 7.16(1 H, ddd, J = 3223-crystal 273 6 nm) · 7,7,2 Hz, Ar—H) · 7.23(1 H,dd, J =   1618-1599 ε max7,2 Hz, Ar—H) · 7662 (λ max 7.27(1 H, ddd, J = 7,7,2 Hz, Ar—H) · 253.2nm) · 7.34(1 H, d, J = 7.2 Hz, Ar—H) · ε max 10.01(1 H, br, OH) ·11.53(1 H, br, OH) · 32958 (λ 12.25(1 H, brs, OH) max 205.2 nm) 254.02(3 H, s, CH3) · 4.26(2 H, s, CH2) · DMSO-d6  3352(OH)-    pinkish27l(M+, ε max 15241 6.16(1 H, d, J = 2 Hz, Ar—H) ·  2935(CH)-     whitebase)-211 (λ max 6.39(1 H, d, J = 2 Hz, Ar—H)  1634(CN)-     needle283.6 nm) · · 7.22-7.41(4 H, m, Ar—H) · 1597 crystal ε max 10.21(1 H,br, OH) · (aroma) 7228 (λ max 11.63(1 H, brs, OH) 255.2 nm) · ε max 3726(λ max 204.4 nm) 26 181.1-184.9 2.98-3.01(2 H, m, CH2) · 3.28- DMSO-d63429- 278 ε max 11694 3.11(2 H, m, CH2) ·   3370-1608 (M+, (λ max 6.30(1H,d,J = 2 Hz, Ar—H) · base)- 276.8 nm) · 6.35(1 H, d, J = 2 Hz, Ar—H) ·263 (M +− ε max 7.25(1 H, dd, J = 8.2 Hz, Ar—H) · 155-245 58928 (λ max7.43(1 H, d, J = 2 Hz, Ar—H) · (M+− 202.0 nm) 7.48(1 H, d, J = 8 Hz,Ar—H) 33)-210 · 9.31(1 H, s, OH) · 9.55(1 H, s, OH) (M+− 68) 27127.3-130.7 3.03-3.06(2 H, m, CH2) · DMSO-d6 3368- 278 ε max 88813.42-3.45(2 H, m, CH2) · 1593- (M+, (λ max 275.2 6.32(1 H, d, J = 2 Hz,Ar—H) · base)- nm) · ε 6.36(1 H, d, J = 2 Hz, Ar—H) 263 (M+− max 55704 ·7.21(1 H, t, J = 8 Hz, Ar—H) · 15)-245 (λ max 7.48(2 H, t, J = 8 Hz,Ar—H) · (M+− 204.4 nm) 9.35(1 H, brs, OH) · 33)-243 9.57(1 H, brs, OH)(M+− 3.5)-210 (M+− 68) 28 182.9-184.4 2.45(3 H, s, CH3) · 6.30(1 H, d, J= 3340- plate 288(M+, λ max nm 1.9 Hz, Ar—H) ·   1599-1575 crystalBase)- (ε) · 6.33(1 H, d, J = 1.8 Hz, Ar—H) · 256-241 239.6 (29100) ·6.79(1 H, d, J = 12.4 Hz, CH—H) 276.4 7.05(1 H, d, J = 12.4HZ, CH—H) ·(26000) · 3264 7.20(2 H, m, J = 5.2 Hz, Ar—H) · (8300) 7.29(1 H, d, J =3.6 Hz, Ar—H) 9.66(1 H, s, OH) 9.83(1 H, s, OH) · 29 237.4-238.63.04-3.07(2 H, m, CH2) · DMSO-d6 3394- white 269 λ max nm 3.27-3.30(2 H,m, CH2) · 2229- needle (M+, (ε) · 6.33(1 H, d, J = 2 Hz, Ar—H) · 1613-crystal base)- 206.0 (49700) · 6.37(1 H, d, J = 2 Hz, Ar—H)   1499-1454254 (M+- 299.6 · 7.64(2 H, s, Ar—H) · 15)-236 (11400) 7.78(1 H, s, Ar—H)· (M +− 33) 9.33(1 H, s, OH) 9.57(1 H, s, OH) 30 0.95(3 H, t, J = 7.3Hz, CH3) · DMSO-d6 3386- pale yellow 302(M+)- ε max 6083 1.99-2.05(1 H,m, CH2) · 3082- needle 226 (Base) (λ max 2.32-2.37(1 H, m, CH2) ·  1671-1586 crystal 321.6 nm) · ε 4.31(1 H, t, J = 6.76 Hz, CH) · max32503 7.21-7.26(1 H, m, Ar—H) (λ max · 7.31(1 H, s, Ar—H) · 244.4 nm) ·7.45-7.52(4 H, m, Ar—H) · ε max 7.63(1 H, m, Ar—H) 37486 (λ max 210.4nm) ·· 31 194.2-196.1 1.67(6 H, s, CH3) · DMSO-d6 3470- orange 285(M+)-ε max 3969 6.8(1 H, s, Ar—H) · 3337- pnsm 272 (Base) (λ max 339.2 7.10(1H, s, Ar—H) ·   1633-1595 nm) · ε 7.24(1 H, t, J = 1 Hz, Ar—H) · max20771 7.54(1 H, t, J = 1.1 Hz, Ar—H) · (λ max 7.59(2 H, dd, J = 8, 260.0nm) 1.3 Hz, Ar—H) ·· ε max 21.049 (λ max 242.0 nm) · ε max 35595 (λ max204.4 nm) · 32 1.01(3 H, t, J = 7.2 Hz, CH3) · DMSO-d6 3339- needle 332-λ max nm 2.02-2.09(1 H, m, CH2) · 2968- crystal 303-285 (ε) ·2.50-2.58(1 H, m, CH2) · 2917- 204.4 (33400) · 4.73(1 H, dd, J = 8.2,6.0 Hz, CH) · 2878- 246.0 5.45(1 H, s, OH) · 6.8(1 H, dd, J =  1621-1590 (22300) · 8.8, 2.5 Hz, Ar—H) · 272.8 (sh 7.04(1 H, m, Ar—H)16300) · · 7.16(1 H, t, J = 295.2 4.4 Hz, Ar—H) · (11200) · 7.36(1 H, d,J = 6.8 Hz, 340.0 Ar—H) · 7.40(1 H, dd J = (6900) 7.2.1 Hz, Ar—H) ·7.64(1 H, dd, J = 8.8, 1.0 Hz, Ar—H) ·8.1 33 2.83(2 H, t, J = 6 Hz, CH2)· DMSO-d6 3524- 2S7 λ max nm 3.07(2 H, t, J = 6 Hz, CH2) · 3298- (M+,(ε) · 4.01(2 H, s, NCH2) · 3156- base)- 206.4 (45100) · 6.12(1 H, d, J =2 Hz, Ar—H) · 2999- 240 (M+− 274.0 6.18(1 H, d, J = 2 Hz, Ar—H) · 2897-17) (3400) 7.19(1 H, d, J = 8 Hz, Ar—H) · 1624- 7.33(1 H, d, J = 8 Hz,Ar—H) · 1605- 7.39(1 H, s, Ar—H) · 1509- 9.29(1 H, s, OH) 9.43(1 H, s,OH)   1496-1458 34 2.99(2 H, t, J = 6 Hz, CH2) · DMSO-d6 3433- 273 λ maxnm 3.28(2 H, t, J = 6 Hz, CH2) · 1595- (M+, (ε) · 3.72(2 H, s, NCH2) ·1560- base)- 204.8 (41200) · 6.27(1 H, d, J = 2 Hz, Ar—H) · 1457- 256 (M+− 275.6 6.34(1 H, d, J = 2 Hz, Ar—H) 17)-223 (8400) · 7.15(1 H, d, J =8 Hz, Ar—H) · (M +− 50) 7.29(1 H, s, Ar—H) · 7.39(1 H, d, J = 8 Hz,Ar—H) · 9.25(1 H, s, OH) 9.47(1 H, s, OH)

TABLE 5 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 35 167.4-168.2 1.02(3 H, t, J = 7 Hz, CH3) · CDCI33340- 332 λ max nm (ε) · 2.01(1 H, sev, J = 7 Hz, CH2) · 2973- (M+,base) 244.4 (22900) · 280.4 2.48(3 H, s, SCH3) · 2912- (25700) · 34882.49(1 H, sev, J = 7 Hz, CH2) · 2879- (7100) 4.83(1 H, t, J = 7 Hz, CH)· 1618- 6.24(1 H, s, Ar—H) · 1594- 6.63(1 H, s, Ar—H) · 1489- 7.04(1 H,dd, J = 8.2 Hz, 1466- Ar—H) 7.17(1 H, s, Ar—H) · 7.53(1 H, d, J = 8 Hz,Ar—H) · ?(1 H, ?, OH) · 13.40(1 H, s, OH) 36 199.6-200.5 0.96(3 H, t, J= 7 Hz, CH3) · DMSO-d6 3487- brown 332(M+, base) λ max nm (ε) · 2.00(1H, sev, J = 7 Hz, CH2) · 3271- powder 207.2 (28200) · 248.8 2.44(1 H,sev, J = 7 Hz, CH2) · 2974- (21100) ·264.0 2.55(3 H, s, SCH3) · 2935-(23800) · 280.8 4.67(1 H, t, J = 7 Hz, CH) · 2914- (21200) · 339.67.00(1 H, s, Ar—H) · 2877- (4700) 7.16(1 H, d, J = 8 Hz Ar—H) 1644-7.19(1 H, s, Ar—H) · 1606- 7.55(1 H, s, Ar—H) · 1586- 7.67(1 H, d, J = 8Hz, Ar—H) · 1499- 9.92(2 H, brs, OH) 1456 37 1.54(3 H, d, J = 6.7 Hz,CH3) · DMSO-d6 3490- λ max nm (ε) · 4.84(1 H, q, J = 6.7 Hz, CH) · 3274-204.4 (22800) · 243.6 6.96(1 H, s, Ar—H) · 1645- (15900) · 257.2 7.24(1H, t, J = 7.4 Hz, Ar—H) · 1601- (15000) · 3384 7.39(1 H, d, J = 7.7 Hz,Ar— 1581- (3700) H) · 7.46(1 H, t, J = 7.4 Hz, Ar—H) · 1509 7.51(1 H, s,Ar—H) · 7.68(1 H, d, J = 7.5 Hz, Ar—H) · 38 175.0-177.5 0.98(3 H, t, J =7 Hz, CH3) · DMSO-d6 3332- 286 ε max 8811 (λ 2.05(1 H, sev, J = 7 Hz,CH2) · 2977- (M+, base)- max 340.0 nm) · ε 2.44(1 H, sev, J = 7 Hz, CH2)· 2887- 271 (M +− max 13046 (λ max 4.84(1 H, t, J = 7 Hz, CH) · 1621-15) - 253 299.6 nm) · ε max 6.23(1 H, d, J = 2 Hz, Ar—H) · 1591- (M +−33)- 25492 (λ max 6.70(1 H, d, J = 2 Hz, Ar— 241.8 nm) · ε max H) ·7.35(1 H, t, J = 8 Hz, Ar—H) · 30052 (λ max 7.46(1 H, d, J = 8 Hz Ar—202.4 nm) H) · 7.57(1 H, t, J = 8 Hz, Ar—H) · 7.77(1 H, d, J = 8 Hz, Ar—H) · 10.97(1 H, brs, OH) 13.30(1H 39 152.1-153.4 1.62(3 H, d, J = 7 Hz,CH3) · DMSO-d6 3271- ε max 8221 (λ 5.09(1 H, q, J = 7 Hz, CH) · 1618-max 340.0 nm) · ε 6.23(1 H, d, J = 2 Hz, Ar—H) · 1594- max 12798 (λ max6.70(1 H, d, J = 2 Hz, Ar—H) 299.2 nm) · ε max · 7.35(1 H, t, J = 8 HzAr—H) · 24627 (λ max 7.49(1 H, d, J = 8 Hz Ar—H) 241.2 nm) · ε max ·7.57(1 H, t, J = 8 Hz, Ar—H) · 44124 (λ max 7.76(1 H, d, J = 8 Hz, Ar—H)202.4 nm) · · 10.96(1 H, brs, OH) 13.41(1 H, s, OH) · 40 67.5-68.33.41-3.47(1 H, m, CH2) · DMSO-d6 3338- yellow 348 λ max nm (ε)·3.73-3.74(1 H, m, CH) · 1620- powder (M+, base)- 241.2 (19600) · 300.85.38-5.40(3 H, m, CH3) · 1583 330 (M +− (10600) · 340.0 6.23(1 H, d, J =2 Hz, Ar—H) · 18)-257 (6500) 6.70(1 H, d, J = 2 Hz, Ar—H) · (M +−91)-229 7.18(1 H, t, J = 8 Hz, Ar—H) · (M +− 119) 7.26-7.42(5 H, m,Ar—H) · 7.55(1 H, t, J = 8 Hz, Ar—H) · 7.66(1 H, d, J = 8 Hz Ar—H) ·7.75(1 H, d, J = 8 Hz Ar—H) · 11.00(1 H, brs, OH) 13.22(1 H, s, OH) · 41190.0-191.6 1.68(3 H, d, J = 6.7 Hz, CH3) · CDCI3 3324- colorless256(M+, ε max 20467 (λ max 4.94(1 H, dd, J = 13.2,6.7 Hz, CH2) · 1656-needle Base) 256.0 nm)·· 5.55(1 H, s, OH) · 1589 crystal 6.76(1 H, dd, J= 8.8.2,2.2 Hz, CH) · 7.05(1 H, d, J = 2.1 Hz Ar—H) · 7.17(1 H, td, J =6.8,2.3 Hz, Ar—H) · (2 H, q, Ar—H) 7.64(1 H, d, J = 7.7 Hz, Ar—H) ·8.13(1 H, d, J = 8.7 Hz, Ar—H) 42 1.01 (3 H, t, J = 7.2 Hz, CH3) · CDCI33398- 286-253-229 ε max 20284 (λ max 2.02-2.09(1 H, m, CH2) · 2969- 244nm) · ε max 2.50-2.58(1 H, m, CH2) · 2877- 34443 ( λ max 4.91(1 H, dd, J= 8.2,6.0 Hz, CH) · 1652- 204.4 nm) 6.1 (2 H, s, OH) · 6.9 1595- (1 H,dd, J = 8.6 Hz, Ar—H) · 1471- 7.04 (1 H .d Ar—H) · 7.16(1 H, m, Ar—H) ·7.36 (1 H, m, Ar—H) · 7.40 (1 H, mAr—H) · 7.64 (1 H,mAr—H) · 7.83 (1 H,d, J = 8.6 Hz, Ar—H) 43 0.77(6 H, t, J = 7 Hz, CH3) · DMSO-d6 3365- 360λ max nm (ε) · 1.98(2 H, six, J = 7 Hz, CH2) 2968- (M+, base)- 254.0(9717) · 284.0 2.25(2 H, six, J = 7 Hz, CH2) · 2923- 345 (M +− (11907) ·362.0 2.54(3 H, s, SCH3) · 2879- 15)-275 (2323) · 6.31 (1 H, d, J = 2 HzAr—H) 1617- (M +− 85) 6.34(1 H, d, J = 2 Hz, Ar—H) 1576- 7.15(1 H, dd, J= 8.2 Hz, Ar—H) · 1457- 7.32(1 H, d, J = 2 Hz, Ar—H) · 7.55(1 H, d, J =8 Hz, Ar—H) 9.96(2 H, brs, OH) · 10.03(2 H, br 44 235.6-237.4 0.87(3 H,t, J = 7.3 Hz, CH3) · 3517- needle 366(M+, λ max nm (ε) · 1.89(1 H, sev,J = 6.8 Hz, CH2) · 3294- crystal pale Base)- 246.4 (30500) · 258 2.35(1H, sev, J = 7.3 Hz, CH2) · 2974- violet 364-333- (sh 27400) · 280 (sh4.59(1 H, t, J = 7.1 Hz, CH) · 2960- 331-309- 16200) · 340.0 6.94(1 H,s, Ar—H) · 2936- 307-285 (6800) · 7.41(1 H, dd,J = 8,2 Hz, Ar—H) 1647-7.44(1 H, s, Ar—H) · 1597- 7.46(1 H, s, Ar—H) · 1586- 7.62(1 H, d, J = 8Hz, Ar—H) · 1507- (2 H, brs, OH) 1461

TABLE 6 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 45 227.2- 0.95(3 H, t, J = 7.2 Hz, CH3) · DMSO-d63516- pinkish- 366 (M+, λ max nm (ε) · 229.9 1.96-2.01(1 H, m, CH2) ·3307- white Base)-364 337.6 (5600) · 280.8 2.38-2.44(1 H, m, CH2) ·2968- needle (12000) · 257.2 4.64(1 H, t, J = 7.2 Hz, CH) · 2877-crystal (25600) · 241.6 7.02(1 H, s, Ar—H) · 1645- (28100) · 205.27.35(1 H, d, J = 8.4 Hz, Ar—H) · 1596- (36100) 7.56(1 H, s, Ar—H) ·1506- 7.71(1 H, dd, J = 1.7, 8.4 Hz, Ar—H) · 1463 7.97(1 H, d, J = 1.7Hz, Ar—H) · 10.04(2 H, brs, OH) · 46 179.8- 0.98(3 H, t, J = 7 Hz, CH3)· DMSO-d6 3514- λ max nm (ε) 183.0 2.04(2 H, m, J = 7 Hz, CH2) · 3289-2.25(2 H, m, J = 7 Hz, CH2) · 2970- 2.44(1 H, sev, J = 7 Hz, CH2) ·2936- 2.47(3 H, s, SCH3) · 2877- 4.71(1 H, t, J = 7 Hz, CH) · 1645-6.40(2 H, brs, OH) · 1598- 7.00(1 H, m, Ar—H) · 1505 7.10(1 H, m, J = 8Hz, Ar—H) 7.16(1 H, m, Ar—H) · 7.22(1 H, m, Ar—H) · 7.54(1 H, s, Ar—H) ·7.90(2 H, brs, OH) · 8.01(1 H, 47 121.0- 0.850(3 H, t, J = 7.5 Hz, −CH3)· DMSO-d6 3328- colorless ε max 7180 (λ max 123.0 1.540(2 H, Sx, J = 7.5Hz, 2959- needle 325.2 nm) · −CH3) · 2.509(2 H, t, 7.5 Hz, −CH2) · 2929-crystal ε max 6924 (λ max 4.044(2 H, s, CH2) · 2869- 313.6 nm) · 6.063(1H, d, J = 2.2 Hz, Ar—H) · 1636- ε max 15843 (λ 6.337(1 H, d, J = 2.2 Hz,Ar—H) · 1592- max 287.2 nm) · ε 7.094(1 H, dd, J = 8.1, 1.4 Hz, Ar—H) ·1498- max 4214 (λ max 7.204(1 H, d, J = 8.1 Hz, Ar—H) · 1445 253.2 nm) ·7.214(1 H, s, Ar—H) · ε max 40043 (λ 10.969(1 H, s, Ph—OH) max 204.0 nm)48 179.1- 1.22(3 H, t, J = 8 Hz, CH3) · CDCI3 3315- colorless 286 (M+, λmax nm (ε) · 180.1 2.64(2 H, q, J = 8 Hz, CH2) · 2964- needle base)241.2 (21400) · 262.8 4.35(2 H, brs, CH2) · 2931- crystal (14700) ·301.6 5.76(1 H, brs, OH) · 2872- (11200) · 340.0 6.25(1 H, d, J = 2 Hz,Res-H) · 1618- (7800) 6.67(1 H, d, J = 2 Hz, Res-H) · 1594 7.06(1 H, dd,J = 8,1 Hz, Ar—H) · 7.27(1 H, d, J = 1 Hz Ar—H) · 7.52(1 H, d, J =8,Ar—H) · 13.53(1 H, s, OH) 49 1.15(3 H, t, J = 7.1 Hz, CH3) · DMSO-d63339- amorphous 270-241 λ max nm (ε) · 2.58(2 H, q, J = 7.1 Hz, CH2) ·2968- 287.2 (12600) · 327.2 4.03(2 H, s, CH2) · 2932- (6700) 6.07(1 H,d, J = 2.5 Hz, Ar—H) · 1637- 6.36(1 H, d, J = 2.5 Hz, Ar—H) · 1597-7.05-7.25(3 H, m, Ar—H) · 1506- 11.00(1 H, brs, OH) · 1446 13.00(1 H, s,OH) 50 105.6- 0.94(3 H, t, J = 7 Hz, CH3) · DMSO-d6 3314- white 298 λmax nm (ε) · 106.8 1.33(2 H, Sx, J = 7 Hz, CH2) · 2956- needle (M+,base)- 204.4 (36300) · 220.0 1.58(2 H, quintet, J = 7 Hz, CH2) · 2929-crystal 269 (M +− (sh.28100) · 287.2 2.61 (2 H, t, J = 7 Hz, CH2) ·2860- 29)-255 (15000) · 326.0 4.11(2 H, s, CH2) · 1636- (M +− 43)-241(6900) 6.13(1 H, d, J = 2 Hz, Ar—H) · 1498- (M +− 57) 6.40(1 H, d, J = 2Hz, Ar—H) · 1445- 7.16(1 H, d, J = 8 Hz, Ar—H) · 7.28(2 H, dd, J = 8.2Hz, Ar—H) · 11.05(1 H,brs, Ph—OH) · 13.07(1 H, s, Ph—OH) 51 125.9- 2.9(4H, m, CH2) · 4.02(2 H, s, CH2) · CDCI3 3482- colorless 346(M+)- ε max7420 (λ max 127.7 6.16(1 H, d, J = 2.5 Hz, Ar—H) · 2923- amorphous255(base) 325.2 nm) 6.36(1 H, d, J = 2.5 Hz, Ar— 2859- ε max 7063 (λ maxH) · 7.0-7.3(8 H, m, Ar—H) · 1636- 312.8 nm) 13.04(1 H, s, OH) 1507- εmax 1 4590( λ max 1447 286.8 nm) ε max 6445( λ max 257.2 nm) ε max54184(λ max 204.0 nm) 52 0.91(3 H, t, J = 6 Hz, CH3) · CDCI3 3310- oil298(M+, ε max 7414 (λ max 1.2-1.7(4 H, m, CH2 × 2) · 2959- base)-241324.0 nm) · 2.59(2 H, t, J = 7 Hz, CH2) · 2933- ε max 7140 (λ max 4.02(2H, s, CH2) · 2860- 313.6 nm) · 6.0(1 H, brs, Ph—OH) · 1636- ε max 15675(λ 6.16(1 H, d, J = 2 Hz, Ar—H) · 1595- max 286.8 nm) · ε max 6.38(1 H,d, J = 2 Hz Ar—H) · 1508- 4885(λ max 6.9-7.3(3H , m, Ar—H) · 1445 254.8nm) · 13.04(1 H, s, Ph—OH) ε max 40878 (λ max 204.8 nm) 53 106.9- 0.94(3H,t, J = 7 Hz, CH3) · DMSO-d6 3308- pale 314 (M+, λ max nm (ε) · 108.11.34(2 H, qt, J = 7.7 Hz, CH2) · 2929- yellow base) 204.0 (46000) ·241.6 1.58(2 H, tt, J = 7.7 Hz, CH2) · 2859- needle (22500) · 263.62.64(2 H, t, J = 7 Hz, CH2) · 1618- crystal (15600) · 301.6 4.37(2 H, s,CH2) · 6.24(1 H, d, J = (11 800) · 340.0 2 Hz, Ar—H) · (8000) 6.70(1 H,d, J = 2 Hz, Ar—H) · 6.19(1 H, d, J = 8.2 Hz, Ar—H) · 7.41(1 H, d, J = 2Hz, Ar—H) · 7.62(1 H, d, J = 8 Hz, Ar— H) · 11.02(1 H, brs, OH) ·13.52(1 H, s, OH) 54 170.3- 4.25(2 H, s, CH2) · 6.17(1 H, d, J = DMSO-d63465- colorless 318 (M+, λ max nm (ε) · 172.0 2 Hz, Ar—H) · 3032- needlebase) 204.8 (55366) · 255.6 6.47(1 H, d, J = 2 Hz, Ar—H) · 1644- crystal(25351) · 284.0 7.42(1 H, tt, J = 8.1 Hz, Ar—H) 1592 (sh.16957) · 320.0· 7.48(1 H, d, J = 8 Hz, Ar—H) · (6840) 7.52(2 H, t, J = 8 Hz, Ar—H) ·7.66(1 H, dd, J = 8.2 Hz, Ar—H) · 7.72(2 H, dd, J = 8.1 Hz, Ar—H) ·7.81(1 H, d, J = 2 Hz, Ar—H) · 11.10(1 H, brs, OH) · 13.10(1 H, s, OH)

TABLE 7 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 55 293.9-300.1 4.25(2 H, s, CH2) · 6.16(1 H, d, J =DMSO-d6 3427- yellow 319 (M+, λ max nm (ε) · 2 Hz, Ar—H) · 1637 powderbase) 203.6 (20952) · 256.0 6.46(1 H, d, J = 2 Hz, Ar—H) · (10308) ·279.2 7.50-7.55(2 H, m, Ar—H) · (10274) · 317.5 (3383) 7.73(1 H, d, J =8 Hz, Ar—H) · 7.89(1 H, s, Ar—H) · 8.12(1 H, d, J = 8 Hz, Ar—H) · 8.62(1H, s, Ar—H) · 8.94(1 H, s, Ar—H) · 11.15(1 H, brs, OH) · 13.08(1 H, s,OH) 56 244.3-250.7 4.28(2 H, s, CH2) · 6.16(1 H, d, J = DMSO-d6 3502-colorless 363 (M+, λ max nm (ε) · 2 Hz, Ar—H) · 3085- amorphous base)204.8 (49743) · 255.6 6.47(1 H, d, J = 2 Hz, Ar—H) · 1641- (32260)·327.6 (9997) 7.53(1 H, d, J = 8 Hz, Ar—H) 1593 · 7.79-7.83(2 H, m,Ar—H) · 7.99(1 H, d, J = 2 Hz, Ar—H) · 8.21(1 H, d, J = 8 Hz, Ar—H) ·8.27(1 H, dd, J = 8.2 Hz, Ar—H) · 8.52(1 H, t, J = 2 Hz, Ar—H) · 11.12(1H, brs, OH) · 13.09(1 H, s, OH) 57 171.0-172.7 4.15(2 H, s, CH2) ·6.09(1 H, d, J = DMSO-d6 3543- pinkish 308 (M+, λ max nm (ε) · 2 Hz,Ar—H) · 3468- white base)-279 203.5 (30330) · 220.0 6.38(1 H, d, J = 2Hz, Ar—H) · 3062- needle (M +− 29) (sh.24545) · 282.0 6.59(1 H, dd, J =3.2 Hz, Ar—H) · 1641 crystal (30829) · 320.5 (6430) 6.95(1 H, d, J = 3Hz, Ar—H) · 7.38(1 H, d, J = 8 Hz, Ar—H) · 7.63(1 H, dd, J = 8.2 Hz,Ar—H) · 7.75(1 H, s, Ar—H) · 7.78(1 H, d, J = 2 Hz, Ar—H) · 11 ?(1 H,brs, OH) · 13.00(1 H, s, OH) 58 199.9-201.0 4.17(2 H, s, CH2) · 6.10(1H, d, J = DMSO-d6 3369- pale yellow 324(M+, base) λ max nm (ε) · 2 Hz,Ar—H) · 3111- needle 203.6 (3996) · 225.0 6.38(1 H, d, J = 2 Hz, Ar—H) ·1645- crystal (sh.26343) · 284.4 7.13(1 H, dd, J = 4.5 Hz, Ar—H) 1601-(33237) · 3300 · 7.37(1 H, d, J = 8 Hz, Ar—H) · (sh,7905) 7.51(1 H, dd,J = 4.1 Hz, Ar—H) · 7.55(1 H, dd, J = 5.1 Hz, Ar—H) · 7.59(1 H, dd, J =8.2 Hz, Ar—H) · 7.76(1 H, d, J = 2 Hz, Ar—H) · 11.?(1 H, brs, OH) ·13.01(1 H, s, OH). 59 >300 4.23(2 H, s, CH2) · 5.21(2 H, brs, NH2) ·DMSO-d6 3368- pale yellow 333(M+, base) λ max nm (ε) · (decom- 6.15(1 H,d, J = 2 Hz, Ar—H) · 3280- plate 206.4 (35877) · 229.5 position) 6.45(1H, d, J = 2 Hz, Ar—H) · 1641- crystal (sh.27582) · 285.0 6.62(1 H, dd, J= 8.2 Hz, Ar—H) · 1606 (12124) · 319.0 6.82(1 H, d, J = 8 Hz, Ar—H) ·(sh.6503) 6.88(1 H, d, J = 2 Hz, Ar—H) · 7.14(1 H, t, J = 8 Hz, Ar—H) ·7.44(1 H, d, J = 8 Hz, Ar—H) · 7.52(1 H, dd, J = 8.2 Hz, Ar—H) · 7.67(1H, d, J = 2 Hz, Ar—H) · ?(1 H, brs, OH) · 13.09( 60 174.0-175.0 2.34(2H, s, CH3) · 4.17(2 H, s, CH2) · DMSO-d6 3503- pale yellow 332(M+, base)λ max nm (ε) · 6.09(1 H, d, J = 2 Hz, Ar—H) · 3031- powder 206.0 (53935)· 260.4 6.39(1 H, d, J = 2 Hz, Ar—H) · 2917- (27534) · 320.8 (7109)7.26(2 H, d, J = 8 Hz, Ar—H) · 1640- 7.39(1 H, d, J = 8 Hz, Ar—H) · 15917.54-7.58(3 H, m, Ar—H) · 7.72(1 H, d, J = 2 Hz, Ar—H) · ?(1 H, brs, OH)· 13.04(1 H, s, OH) 61 208.9-213.6 4.19(2 H, s, CH2) · 6.10(1 H, d, J =DMSO-d6 3503- pale brown 352 λ max nm (ε) · 2 Hz, Ar—H) · 2919- powder(M+, base) 212.0 (52265) · 258.8 640(1 H, d, J = 2 Hz, Ar—H) · 1645-(24168) · 280.0 7.40-7.43(2 H, m, Ar—H) · 1593 (sh.17980) · 319.0 7.48(1H, t, J = 8 Hz, Ar—H) · (6840) 7.63-7.66(2 H, m, Ar—H) · 7.74(1 H, t, J= 2 Hz, Ar—H) · 7.82(1 H, d, J = 2 Hz, Ar—H) · ?(1 H, brs, OH) · 1303(1H, s, OH) 62  91.8-94.8 2.21(2 H, s, CH3) · 4.16(2 H, s, CH2) · DMSO-d63556- yellow 332 λ max nm (ε) · 6.11(1 H, d, J = 2 Hz, Ar—H) · 3467-powder (M+, base) 207.6 (50567) · 2868 6.41(1 H, d, J = 2 Hz, Ar—H) ·3060- (14377) · 3220 (6601) 7.18(1 H, dd, J = 7,2 Hz, Ar—H) · 1637-7.17-7.21(4 H, m, Ar—H) · 1602 7.39(1 H, d, J = 8 Hz, Ar—H) · 741(1 H,d, J = 2 Hz, Ar—H) · ?(1 H, brs, OH) · 1304(1 H, s, OH) 63 151.5-155.01.20(3 H, t, J = 7.1 Hz, CH3) · DMSO-d6 3314- 346-332- λ max nm (ε) ·2.2(4 H, m, CH2) · 1629 285-275 286.8 (14800) · 4.03(2 H, s, CH2) ·6.16(1 H, d, J = 2.5 Hz, Ar—H) · 6.38(1 H, d, J = 2.5 Hz, Ar—H) · 6.55(1H, brs, OH) · 7.0- 7.7(8 H, m, Ar—H) · 13.02(1 H, s, OH) 64 191 7-195.04.21(2 H, s, CH2) · 6.10(1 H, d, J = DMSO-d6 3502- white 386 λ max nm(ε) · 2 Hz, Ar—H) · 3057- needle (M+, base) 208.0 (50083) · 257.6 6.41(1H, d, J = 2 Hz, Ar—H) · 1647- crystal (23573) · 280.0 7.45(1 H, d, J = 8Hz, Ar— 1594 (sh.18210) · 321.0 H) · 7.68-7.74(3 H, m, Ar—H) · (6975)7.89(1 H, dt, J = 8. 2 Hz, Ar—H) · 7.98-8.00(2 H, m, Ar—H) · ?(1 H, brs,OH) · 13.04(1 H, s, OH) 65 274.0- 2.67(2 H, s, CH3) · 4.27(2 H, s, CH2)· DMSO-d6 3195- pinkish- 360(M+, base) λ max nm (ε) · 279.0 6.16(1 H, d,J = 2 Hz, Ar—H) · 1677- white 204.8 (44022) · 285.6 (decom- 6.47(1 H, d,J = 2 Hz, Ar—H) · 1641- powder (32630) position) 7.52(1 H, d, J = 8 Hz,Ar—H) · 1606 7.76(1 H, dd, J = 8.2 Hz, Ar—H) · 7.88-7.92(3 H, m, Ar—H) ·8.09(2 H, d, J = 8 Hz, Ar—H) · ?(1 H, brs, OH) · 13.09(1 H, s, OH) 66173.8-175.8 1.60-1.61(4 H, m, CH2 * 2) · DMSO-d6 3322- mud brown364(M+)- ε max 16815 (λ max 2.16(2 H, m, CH2) · 2940- amorphous109(Base)- 286.4 nm) · 2.30(2 H, m, CH2) · 1640- 81 ε max 10407 (λ4.05(2 H, s, CH2) · 1606 max 4.11(2 H, s, CH2) · 262.4 nm) 6.13(1 H, d,J = 2 Hz, Ar—H) · 6.41(1 H, d, J = 2 Hz, Ar—H) · 7.16(1 H, d, J = 8.2Hz, Ar—H) · 7.23(1 H, t, J = 4 Hz, CH) · 7.26(1 H, d, J = 2 Hz, Ar— H) ·7.29(1 H, d, J = 8 Hz, Ar—H) · 11.0(1 H, br, OH) · 13.05(1 H, s, OH)

TABLE 8 Example melting point NMR Appear- No (centi degree) NMR solventIR ance Mass UV 67 228.4-230.8 2.44(2 H, s, Ar—CH3) · DMSO-d6 3210-white λ max nm 2.64(2 H, s, CH3) · 2977- powder (ε) · 207.6 4.20(2 H, s,CH2) · 2926- (46800) · 6.10(1 H, d, J = 1637- 238,0 2 Hz, Ar—H) · 1591-(sh.37400) · 6.41(1 H, d, J = 1508- 261.0 2 Hz, Ar—H) · 1446 (sh.6300) ·7.37(1 H, dd, J = 284.0 8.2 Hz, Ar—H) · (sh.19000) · 7.43(1 H, d, J =3224 8 Hz, Ar—H) · (9400) 7.68(1 H, dt, J = 8.2 Hz, Ar—H) · 7.73(1 H,dt, J = 8.2 Hz, Ar—H) · 7.85(1 H, d, J = 2 Hz, Ar—H) · 8.05(1 H, d, J =2 Hz, Ar—H) · 11.05(1 H, brs, OH) · 13 68 195.5-195.8 1.57-1.61(4 H, m,CH2 * 2) · DMSO-d6 3244- pale 364 ε max 15975 2.16(2 H, m, CH2) · 2938-yellow (M+)- (λ max 2.31(2 H, m, CH2) · 2874- amor- 255- 287.2 nm) ·4.09(2 H, s, CH2) · 1629- phous 109- ε max 4.12(2 H, s, CH2) · 1507- 817762 (λ max 6.14(1 H, d, J = 1447 261.6 nm) · 2 Hz, Ar—H) · ε max 6.41(1H, d, J = 46059 (λ 2 Hz, Ar—H) · max 206.0 nm) 7.11(1 H, d, J = 8. 2 Hz,Ar—H) · 7.21(1 H, m, CH) · 7.26(1 H, m, Ar—H) · 7.39(1 H, d, J = 8 Hz,Ar—H) · 11.0(1 H, br, OH) · 13.07(1 H, s, OH) 69 199.9-201.4 4.22(2 H,s, CH2) · DMSO-d6 3354- color- 352(M+, ε max 6.16(1 H, d, J = 1634- lessBase)- 7572 (λ 2.3 Hz, Ar—H) · 1605 needle max 322.4 6.50(1 H, d, J =crystal nm) · ε 2.3 Hz, Ar—H) · max 16068 7.48-7.83(7 H, m, Ar—H) · (λmax 11.11(1 H, brs, OH) · 284.4 nm) · 13.08(1 H, s, OH) ε max 21047 (λmax 257.2 nm) 70 249.6-250.8 4.18(2 H, s, CH2) · DMSO-d6 3250- yellow308(M+)- ε max 6.16(1 H, d, J = 1633- needle 279 (Base) 10430.2 (λ 2.1Hz, Ar—H) ·  884 crystal max 320.2 6.49(1 H, d, J = nm) · ε 2.1 Hz,Ar—H) · max 30636.9 6.67(1 H, q, J = ( λ max 1.6 Hz, Furyl-H) · 279.6nm) · 71(1 H, d, J = 3.4 Hz, Furyl-H) · 7.53(1 H, d, J = 7.9 Hz, Ar—H) ·7.63(1 H, d, J = 7.9 Hz, Ar—H) · 7.72(1 H, s, Ar—H) · 7.82(1 H, s, Ar—H)· 11.11(1 H, brs, OH) · 13.06(1 H, s, OH). 71 208.8-210.2 2.4(3 H, s,CH3) · DMSO-d6 3328- yellow 332(M+, ε max 4.2(2 H, s, CH2) · 1636-needle Base) 7458 (λ 6.16(1 H, d, J = 2.3 Hz, Ar—H) · 1595 crystal max320.6 6.49(1 H, d,J = 2.3 Hz, Ar—H) · nm) · ε 7.33(2 H, d, J = 8.0 Hz,Ar—H) · max 23077 7.53-7.69(5 H, m, Ar—H) · (λ max 11.10(1 H, brs, OH) ·262.2 nm) · 1309(1 H, s, OH) 72 163.5-165.8 2.28(3 H, s, CH3) · DMSO-d63377- pinkish- 332(M+, ε max 4.22(2 H, s, CH2) · 1633- white Base) 6656(λ 6.16(1 H, d, J = 1.3 Hz, Ar—H) · 1591 amor- max 322.0 6.46(1 H, d, J= 1.2 Hz, Ar—H) · phous nm) · ε 7.24-7.56(7 H, m, Ar—H) · max 1465511.09(1 H, brs, OH) · (λ max 13.1(1 H, s, OH) 287.0 nm) · 73 183.0-184.74.23(2 H, s, CH2) · DMSO-d6 3290- pale 386(M+, ε max 6.17(1 H, d, J =1633- yellow Base) 7394 (λ 2.2 Hz, Ar—H) · 1594- needle max 323.2 6.51(1H, d, J = 2.1 Hz, Ar—H) · 1336 crystal nm) · ε 7.60-7.85(5 H, m, Ar—H) ·max 16194 8.08(2 H, d, J = 1.9 Hz, Ar—H) · (λ max 11.11(1 H, brs, OH) ·286.0 nm) · 13.07(1 H, s, OH) ε max 21318 (λ max 256.2 nm) 74228.3-230.0 4.19(2 H, s, CH2) · DMSO-d6 3393- yellow 333(M+, ε max5.22(2 H, brs, NH2) · 3309- amor- Base) 9332 (λ 6.16(1 H, d, J = 2.2 Hz,Ar—H) · 1637- phous max 322.0 6.49(1 H, d, J = 2.4 Hz, Ar—H) · 1572 nm)· ε 6.62-6.65(1 H, m, Ar—H) · max 14937 6.87(2 H, t, J = 13.8 Hz, Ar—H)· (λ max 7.15(1 H, t, J = 7.8 Hz, Ar—H) · 287.4 nm) · 7.46-7.56(3 H, m,Ar—H) ε max · 11.09(1 H, brs, OH) · 34865 13.09(1 H, s, OH) · (λ max223.4 nm) 75 241.0-247.08 4.25(2 H, s, CH2) · DMSO-d6 crude crude 6.15(1H, d, J = (CNS-183- (CNS-183- 2 Hz, Ar—H) · 20% ) 20% ) · 6 46(1 H, d, J= 2 Hz, Ar—H) · 7.39-7.51(3 H, m, Ar—H) · 7.55- 7.70(2 H, m, Ar—H) ·7.74(1 H, dt, J = 8. 2 Hz, Ar—H) · 7.94(1 H, s, Ar—H) · 8.38(1 H, s, OH)· 10.32(1 H, s, OH) · 11.?(1 H, brs, OH) · 13.09(1 H, s, OH) 76240.1-246.1 4.46(2 H, s, CH2) · DMSO-d6 3331- 340 λ max 6.25(1 H, d, J =3091- (M+, nm (ε) · 2 Hz Ar—H) · 1598 base)- 244.4 6.72(1 H, d, J = 2Hz, Ar—H) · 307 (M +− (22300) · 7.22(1 H, dd, J = 33)-279 297.2 5.4 Hz,Ar—H) · (M +− 61) (30000) · 7.62-7.68(3 H, m, Ar—H) · 343.0 7.74(1 H, d,J = 8 Hz, Ar—H) · (sh.1000) 7.95(1 H, s, Ar—H) · 11.08(1 H, brs, OH) ·13.52(1 H, s, OH) 77 212.6-215.7 4.49(2 H, s, CH2) · DMSO-d6 3619- 350 λmax 6.26(1 H, d, J = 3478- (M+, nm (ε) · 2 Hz, Ar—H) · 3393- base) 268.06.74(1 H, d, J = 2 Hz Ar—H) · 3184- (19100) · 7.46(1 H, t, J = 7 HzAr—H) · 1640- 287.6 7.54(2 H, t, J = 7 Hz, Ar—H) · 1601 (20900) · 7.66(1H, dd, J = 322.0 8.2 Hz, Ar—H) · (7400) 7.76(2 H, d, J = 7 Hz, Ar—H) ·7.81(1 H, d, J = 8 Hz, Ar—H) · 7.91(1 H, d, J = 2 Hz, Ar—H) · 11.06(1 H,brs, OH) · 13.55(1 H, s, OH)

TABLE 9 Example melting point NMR Appear- No (centi degree) NMR solventIR ance Mass UV 78 190.8-195.3 4.49(2 H, s, CH2) · 6.26(1 H, d, J =DMSO-d6 3332- 334 λ max nm (ε)· 2 Hz, Ar—H) · 3073- (M+, 246.4 (26400) ·282.4 6.74(1 H, d, J = 2 Hz, Ar—H) · 1598 base)- (20800) · 344.0 (6900)7.46(1 H, t, J = 7 Hz, Ar—H) · 301 (M +− 7.54(2 H, t, J = 7 Hz, Ar—H) ·33) 7.66(1 H,dd, J = 8.2 Hz, Ar—H) · 7.76(2 H, d, J = 7 Hz, Ar—H) ·7.81(1 H, d, J = 8 Hz, Ar—H) · 7.91(1 H, d, J = 2 Hz, Ar—H) · 11.07(1 H,brs, OH) · 13.55(1 H, s, OH) 79 >250 4.27(2 H, s, CH2) · 6.16(1 H, d, J= DMSO-d6 3370- 394 ε max 52384.9 (λ max (decom- 2 Hz, Ar—H) · 1638 (M+,283.0 nm) · ε max position) 6.47(1 H, d, J = 2 Hz, Ar—H) · base) 88456.4(λ max 7.43-7.56(4 H, m, Ar—H) · 208.4 nm) 7.73(1 H, dd, J = 8.2 Hz,Ar—H) · 7.79-7.83(6 H, m, Ar—H) · 7.88(1 H, d, J = 2 Hz, Ar—H) · 11.08(1H, brs, OH) · 13.01(1 H, s, OH) 80 >250 4.51(2 H, s, CH2) · 6.26(1 H, d,J = DMSO-d6 3421- 379 λ max nm (ε) · (decom- 2 Hz, Ar—H) · 3090- (M+,247.6 (45100) · 282.7 position) 6.74(1 H, d, J = 2 Hz, Ar—H) · 2911-base)- (27100) · 340.0 (10900) 7.77-7.88(3 H, m, Ar—H) · 2360- 346 (M +−8.67(1 H, s, Ar—H) · 1617 33) 8.24(1 H, d, J = 8 Hz, Ar—H) · 8.30(1 H,dd, J = 8.2 Hz, Ar—H) · 8.55(1 H, d, J = 2 Hz, Ar—H) · 11.06(1 H, brs,OH) · 13.55(1 H, s, OH) · 81 214.3-215.3 4.37(2 H, s, CH2) · 6.21(1 H,d, J = DMSO-d6 3310- pale ε max 7707 (λ max 2.4 Hz, Ar—H) · 1616- yellow340.0 nm) · ε max 6.69(1 H, d, J = 2.3 Hz, Ar—H) · 1591- amor- 19923 (λmax 7.14(1 H, dd, J = 5.2, 3.7 Hz,  701 phous 286.4 nm) · ε max Ar—H) ·7.54- 14694 (λ max 7.6(3 H, m, Ar—H) · 7.71(1 H, dd, 241.6 nm) · ε max J= 7.9, 1.9 Hz, Ar— 17445 (λ max H) · 7.95(1 H, d, J = 1.9 Hz, 204.8 nm)Ar—H) · 13.46(1 H, s, OH) 82 234.9-238.8 4.36(2 H, s, CH2) · 6.20(1 H,d, J = DMSO-d6 3226- pinkish- 324(M+, ε max 9678 ( λ max 2.4 Hz, Ar—H) ·1611- white Base) 340.0 nm) · ε max 6.60(1 H, dd, J = 3.4, 1.9 Hz, 1575-amor- 29245 (λ max Ar—H) · 885 phous 282.0 nm) · ε max 6.68(1 H, d, J =24 Hz, Ar—H) · 17358 (λ max 7.06(1 H, d, J = 3.2 Hz Ar—H) · 239.2 nm) ·ε max 7.55(1 H, d, J = 6 Hz, Ar—H) · 17404 (λ max 7.75(2 H, dd, J = 7.7,1.7 Hz, 204.8 nm) Ar—H) · 7.99(1 H, d, J = 1.6 Hz, Ar—H) · 13.46(1 H, s,OH) · 83 >200 4.47(2 H, s, CH2) DMSO-d6 3364- 349 λ max nm (ε)- (decom-5.25(2 H, s, NH2) · 3295- (M+, 204.8 (30900) · 243.6 position) 6.25(1 H,d, J = 2 Hz, Ar—H) · 1582 base) (26500) · 281.6 6.65(1 H, d, J = 8 Hz,Ar—H) (161 00) · 337.0 (6400) 6.73(1 H, d, J = 2 Hz, Ar—H) · 6.86(1 H,d, J = 8 Hz, Ar—H) · 6.92(1 H, s, Ar—H) · 7.17(1 H, t, J = 8 Hz, Ar—H) ·7.54(1 H, d, J = 8 Hz, Ar—H) · 7.77(2 H, m, Ar—H) · 11.02( 84 243.5-4.45(2 H, s, CH2) · 6.26(1 H, d, J = DMSO-d6 3338- 324 λ max nm (ε)·248.4 2 Hz, Ar—H) · 3075- (M+, 238.0 (sh.49100) · (decom- 6,68(1 H, dd,J = 3.2 Hz, Ar—H) · 1598 base)- 298.4 (26600) · 339.0 position) 6.72(1H, d, J = 2 Hz, Ar—H) · 295 (21100) 7.15(1 H, d, J = 3 Hz, Ar—H) (M +− ·7.67(1 H, dd, J = 8,2 Hz, 29)-291 Ar—H) · 7.76(1 H, d, J = (M +− 8 Hz,Ar—H) · 7.85(1 H, s, Ar—H) · 33)-263 7.92(1 H, s, Ar—H) · 11.05(1 H, s,OH) · (M +− 61) 13.51(1 H, s, OH) 85 798.3-203.2 4.25(2 H, s, CH2) ·6.15(1 H, d, J = DMSO-d6 3467- 402 λ max nm (ε) · 2 Hz, Ar—H) · 3069-(M+, 251.7 (19600) · 281.5 6.46(1 H, d, J = 2 Hz, Ar—H) · 1650- base)(sh.45900) · 323.0 7.49-7.52(3 H, m, Ar—H) 1594 (68000) · 7.69(1 H, dd,J = 8.2 Hz, Ar—H) · 7.84-7 86(3 H, m, Ar—H) · 11.06(1 H, m, OH) ·13.09(1 H, s, OH) 86 228.4-235.2 2.34(3 H, s, CH3) · 4.38(2 H, s, CH2) ·DMSO-d6 3318- pale 348 ε max 10566 (λ max 6.21(1 H, d, J = 2.3 Hz, Ar—H)· 1619- yellow (M+, 342.2 nm) · ε max 6.69(1 H, d, J = 2.4 Hz, Ar—H) ·1589 amor- Base) 36653 (λ max 7.27(2 H, d, J = 8 Hz, Ar—H) · phous 259.4nm) · ε max 7.58(3 H, t, J = 7.6 Hz, Ar—H) · 70816 (λ max 7.71(1 H, dd,J = 7.9, 1.8 Hz, 203.8 nm) · Ar—H) · 7.92(1 H, d, J = 1.8 Hz, Ar—H) ·13.48(1 H, s, OH) · 87 209.7-212.0 4.36(2 H, s, CH2) ·6.21(1 H, s, CH2)· DMSO-d6 3295- pale 334 ε max 8621 (λ max 6.7(1 H, s, Ar—H) · 1618-yellow (M+, 340.0 nm) · ε max 7.39-7.95(7 H, m, Ar—H) · 1590 needleBase) 13242 (λ max 7.94(1 H, s, Ar—H) · crystal 300.8 nm) · ε max13.48(1 H, s, OH) · 35927 ( λ max 245.2 nm) · ε max 64276 (λ max 2056nm) 88 124.0-125.8 4.19(2 H, s, CH2) · 6.46(1 H, s, DMSO-d6 3401- yellow334 ε max 16414 (λ max Ar—H) · 7.36- 1640- needle (M+, 295.6 nm) · ε max7.74(8 H, m, Ar—H) · 1600 crystal Base) 34018 (λ max 12.98(1 H, s, OH) ·248.8 nm) · ε max 71778 (λ max 204.4 nm)

TABLE 10 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 89 178.1-198.3 2.21(3 H, s, CH3) · DMSO-d6 3340- paleyellow 348 ε max 11569 (λ 4.40(2 H, s, CH2) · 1591 amorphous (M+, Base)max 340.0 nm) · ε 6.21(1 H, s, J = needle max 12408 (λ max 2.3 Hz, Ar—H)· crystal 300.0 nm) · ε max 6.67(1 H, s, J = 36540 (λ max 2.3 Hz, Ar—H)· 241.2 nm) · ε max 7.20-7.62(7 H, m, Ar—H) · 70476 (λ max 13.48(1 H, s,OH) · 203.2 nm) 90 180.3-191.6 4.46(2 H, s, CH2) · DMSO-d6 3329- brown368 ε max 6061 (λ 6.26(1 H, d, J = 2.1 Hz Ar—H) · 1617- needle (M+,Base) max 340.0 nm) · ε 6.74(1 H, d, J = 2.2 Hz, Ar—H) · 1594- crystalmax 9184 (λ max 7.49-8.06(7 H, m, Ar—H) ·  782 amorphous 298.4 nm) · εmax 11.07(1 H, brs, OH) · 23829 (λ max 13.52(1 H, s, OH) 240.0 nm) · εmax 46353 (λ max 210.0 nm) 91 225.3-226.5 4.48(2 H, s, CH2) · 6.26(1 H,d, J = DMSO-d6 3314- pale brown 402 λ max nm (ε) · 2.3 Hz, CH2) · 1615-needle (M+, Base) 254.4 (32300) · 301.6 6.75(1 H, d, J = 2.4 Hz, Ar—H) ·1588- crystal (12700) · 340.0 7.7-7.90(4 H, m, Ar—H) 1335 (8300) ·8.06-8.13(3 H, q, Ar—H) · 11.08(1 H, brs, OH) · 13.52(1 H, s, OH) 92251.6-253.8 4.48(2 H, s, CH2) · 6.27(1 H, d, J = DMSO-d6 3209- orange374 ε max 27125 (λ max 2.2 Hz, Ar—H) · 3180- needle (M+, Base) 302.0 nm)· ε max 6.77(1 H, d, J = 2.3 Hz, Ar—H) · 1610- crystal 31051 (λ max7.33- 1575 236.4 nm) · 7.74(7 H, m, Ar—H) · 8.03-8.06(1 H, q, Ar—H) ·8.28(1 H, d, J = 1.3 Hz, Ar—H) · 11.13(1 H, brs, OH) · 13.52(1 H, s, OH)93 >250 4.21(2 H, s, CH2) · 6.15(1 H, d, J = DMSO-d6 3459- 350 ε max25618 (λ max 2 Hz, Ar—H) · 3291- (M+, base) 277.6 nm) · ε max 6.44(1 H,d, J = 2 Hz, Ar—H) · 3170- 56647 (λ max 6.86(1 H, d, J = 8 Hz, Ar— 1647206.0 nm) · H) · 6.98(1 H, dd, J = 8.2 Hz, Ar—H) · 7.07(1 H, d, J = 2Hz, Ar—H) · 7.39(1 H, d, J = 8 Hz, Ar—H) · 7.50(1 H, dd, J = 8.2 Hz,Ar—H) · 8.08(1 H, s, Ar—H) · 9.05(1 H, brs, OH) · 9.13(1 H, brs, OH) ·11.07(1 H, brs, OH) · 13.09(1 H, s, OH) · 94 268.4-268.5 4.27(2 H, s,CH2) · 6.17(1 H, d, J = DMSO-d6 3340- ε max 29487 (λ 2 Hz, Ar—H) · 1641max 322.0 nm) · ε 6.47(1 H, d, J = 2 Hz, Ar—H) · max 41425 (λ max 7.33(1H, t, J = 8 Hz, Ar—H) · 307.2 nm) · ε max 7.39(1 H, t, J = 8 Hz, Ar—H) ·41043 (λ max 7.50(1 H, s, Ar—H) · 291.2 nm) · ε max 7.53(1 H, d, J = 8Hz, Ar—H) · 56920 (λ max 7.68(1 H, d, J = 8 Hz, Ar—H) · 205.6 nm) 7.73(1H, d, J = 8 Hz, Ar—H) · 7.93(1 H, dd, J = 8.2 Hz, Ar—H) · 8.08(1 H, s,Ar—H) · 11.13(1 H, brs, OH) · 13.07(1 H, s, O 95 257.9-259.9 4.16(2 H,s, CH2) · 6.10(1 H, d, J = DMSO-d6 3339.2- yellow 358 (M+, ε max 22612(λ max 2.3 Hz, Ar—H) · 1633.9- needle Base)-329 323 nm) · ε max 6.46(1H, d, J = 2.4 Hz, Ar—H) · 1609.8- crystal 30616 (λ max 307.6 7.28(1 H,t, J = 7.4 Hz, Ar—H) ·  881.6 nm) · ε max 31103 7.33(1 H, m, Ar—H) · (λmax 290.0 nm) · 7.53(1 H, s, Ar—H) · ε max 52850 (λ 7.57(1 H, d, J =7.9Hz, Ar—H) · max 204.8 nm) 7.65(2 H, q, Ar—H) · 7.81 (1 H, dd, J = 7.8,1.5 Hz, Ar—H) · 7.89(1 H, d, J = 1.3 Hz, Ar—H) · 11.10(1 H, br, OH) ·13.00(1 H, s, OH) 96 261.6-263.2 4.16(2 H, s, CH2) · 6.1(1 H, d, J =DMSO-d6 3347- pale yellow 394 (M+, ε max 45218 (λ max 2.2 Hz Ar—H) ·1633- amorphous Base) 281.2 nm) · ε max 6.45(1 H, d, J = 2.4 Hz, Ar—H) ·1614 83321 (λ max 206.4 7.4(1 H, d, J = 7.3 Hz, Ar—H) · nm) 7.47-7.54(1H, m, Ar—H) · 7.62(1 H, d, J = 1.7 Hz, Ar—H) · 7.72-7.82(7 H, m, Ar—H) ·10.97(1 H, br, OH) · 13.03(1 H, s, OH) 97 197.7-200.8 4.16(2 H, s, CH2)· 6.08(1 H, d, J = DMSO-d6 3258- pale yellow 402 (M+, ε max 11227 (λ max20 Hz, Ar—H) · 6.41(1 H, d, J = 1629- needle Base) 322.8 nm) · ε max 2.2Hz, Ar—H) · 1586- crystal 20844 (λ max 7.44(2 H, d, J = 8.3 Hz, Ar—H) ·1263 280.4 nm) · ε max 7.52-7.59(2 H, m, Ar—H) · 29734 (λ max 252.47.69(1 H, s, Ar—H) · nm) · ε max 75178 7.82(2 H, d, J = 8.6 Hz, Ar—H) ·(λ max 203.6 nm) 11.05(1 H, br, OH) · 13.02(1 H, s, OH) 98 229.8-231.64.10(2 H, s, CH2) · 6.08(1 H, d, J = DMSO-d6 3288- pale brown 350 (M+, εmax 24641 (λ max 2.3 Hz, Ar—H) · 1641- amorphous Base) 286.4 nm) · ε max6.41(1 H, d, J = 2.3 Hz, Ar—H) · 1598 63587 (λ max 6.8(1 H, d, = 8.2 Hz,Ar—H) · 204.4 nm) · 6.96(1 H, dd, J = 6.2,2.2 Hz, Ar—H) · 7.04(1 H, d, J= 2.2 Hz, Ar—H) · 7.39(1 H, dd, J = 7.9,1.5 Hz, Ar—H) · 7.43(1 H, d, J =7.9 Hz, Ar—H) 7.48(1 H, d, J = 1.2 Hz, Ar—H) · 9.01(1 H, br, OH) ·9.13(1 H, br, OH) · 11.03(1 H, 99 pale yellow 340 (M+)- λ max nm (ε) ·amorphous 324-295 207.2(22300) · 227.0 (Base) (22100) · 239.0 (16300) ·287.6 (15500) · 331.2 (6400)

TABLE 11 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 100 239.1-242.6 4.09(2 H, s, CH2) · 6.08(1 H, d, J =DMSO-d6 3467- pale brown 350 (M+, ε max 21818 (λ max 2.3 Hz, Ar—H) ·3256- needle Base) 287.6 nm) · ε max 6.3(1 H, dd, J = 8.3, 2.3 Hz, 1638-crystal 20338 (λ max Ar—H) · 6.37(1 H, d, J = 1593 265.6 nm) · ε max 2.2Hz, Ar—H) · 63304 (λ max 202.4 6.40(1 H, d, J = 2.3 Hz, Ar—H) · nm)7.07(1 H, d, J = 8.4 Hz, Ar—H) · 7.34(1 H, dd, J = 7.8, 1.3 Hz, Ar—H) ·7.37(1 H, d, J = 7.9 Hz, Ar—H) · 7.44(1 H, d, J = 0.9 Hz, Ar—H) · 9.38(1H, br, OH) · 9.47(1 H, s, OH) · 11(1 H, br, O 101 189.4-191.1 4.23(2 H,s, CH2) · 6.17(1 H, d, J = DMSO-d6 3348- pale yellow 342(M+, ε max 40436(λ max 2.4 Hz, Ar—H) · 1633- amorphous Base) 283.6 nm) · 6.48(1 H, d, J= 2.4 Hz, Ar—H) · 1609- ε max 18280 (λ max 7.4-7.6(8 H, m, Ar— 1505249.2 nm) · H) · 11.2(1 H, brs, OH) · 13.04(1 H, s, OH) ε max 56341 (λmax 204.4 nm) 102 135.6-137.6 0.833(3 H, t, J = 6 Hz, CH3) · DMSO-d63434- colorless ε max 3707(λ max 1.15-1.35(6 H, m, CH2) · 3364-amorphous 275.2 nm) · 1.504(2 H, t, J = 6 Hz, CH2) · 2956- ε max 3404 (λmax 2.482(2 H, t, J = 8 Hz, CH2) · 2924- 262.8 nm) · 2.728(2 H, t, J = 6Hz, CH2) · 2855- ε max 52641 (λ max 2.955(2 H, t, J = 6 Hz, CH2) · 1624-206.4 nm) 6.026(1 H, d, J = 2 Hz, Ar—H) · 1498- 6.072(1 H, d, J = 2 Hz,Ar—H) · 1457 6.91-6.97(2 H, m, Ar—H) · 6.700(1 H, s, Ar—H) · 9.127(1 H,s, Ph—OH) · 9.302(1 H, s, Ph—OH) 103 153.3-154.8 1.66(2 H, quintet, J =3 Hz, CH2) · 3423- colorless λ max nm (ε) · 2.49-2.54(2 H, m, CH2) ·3318- amorphous 206.0 (52200) · 275.2 0.73(2 H, t, J = 5 Hz, CH2) ·2939- (3800) 0.73(2 H, t, J = 5 Hz, CH2) · 1618- 2.49-2.54(2 H, m, CH2)· 1497- 4.41(1 H, t, J = 4 Hz, R—OH) · 1461 6.02(1 H, s, Ar—H) · 6.07(1H, s, Ar—H) · 6.95(2 H, s, Ar—H) · 7.01 (1 H, s, Ar—H) · 9.12(1 H, s,Ph—OH) · 9.31(1 H, s, Ph—OH) 104 0.73(3 H, t, J = 7 Hz, CH3) · DMSO-d63338- 284 λ max nm (ε) · 1.13(3 H, d, J = 7 Hz, CH3) · 2961- (M+, base)-206.0 (53000) · 274.4 1.50(2 H, quintet, J = 7 Hz, 2928- 269 (M +−(3900) CH2) · 2.49(1 H, m, CH) · 2873- 15)-255 2.73(2 H, t, J = 6 Hz,CH2) · 1624- (M +− 29) 2.97(2 H, t, J = 6 Hz, CH2) · 1496- 6.03(1 H, d,J = 2 Hz, Ar—H) · 1458 6.07(1 H, d, J = 2 Hz, Ar—H) · 6.96(2 H, m, Ar—H)· 7.01(1 H, m, Ar—H) · 9.13(1 H, s, Ph—OH) · 9.31(1 H, s, Ph—OH) 105125.2-126.9 −0.03(9 H, s, TMS) · DMSO-d6 3360- pale orange λ max nm (ε)· 0.78(2 H, t, J = 8 Hz, CH2) · 2954- needle 205.6 (57600) · 271.22.49-2.53(2 H, m, CH2) · 2923- crystal (4200) 2.72(2 H, m, CH2) · 2854-2.94(2 H, m, CH2) · 6.01(1 H, 1623- d, J = 2 Hz, Ar—H) · 1496- 6.06(1 H,d, J = 2 Hz, Ar—H) · 1457 6.95(2 H, m, Ar—H) · 7.03(1 H, m, Ar—H) ·9.14(1 H, s, Ph—OH) · 9.32(1 H, s, Ph—OH) ·· 106 2.86-2.89(2 H, m, CH2)· DMSO-d6 3402- yellow 349 (Base, λ max nm (ε) · 3.12-3.15(2 H, m, CH2)· 2926- oil M+), 204.4 (60000) 6.18(1 H, d, J = 2858- 252.8 (28700) 2.4Hz, Ar—H) · 1623- 6.21(1 H, d, J = 1508- 2.4 Hz, Ar—H) · 7.41- 14587.43(1 H, m, Ar—H) · 7.55-7.60(2 H, m, Ar—H) · 7.80(1 H, t, J = 8 Hz,Ar—H) · 8.20-8.27(2 H, m, Ar—H) · 8.48-8.49(2 H, m, Ar—H) · 9.25(1 H,br, OH) · 9.44(1 H, br, OH) · 107 2.56-2.57(2 H, m, CH2) · DMSO-d6 3378-pale yellow oil 319 (Base, λ max nm (ε) · 3.08-3.11(2 H, m, CH2) · 2921-M+) 206.0 (57700) 5.19(2 H, brs, NH2) · 2851- 6.17(1 H, d, J = 2.4 Hz,Ar—H) · 1623- 6.18(1 H, d, J = 2.4 Hz, Ar—H) · 1509- 6.61(1 H, dd, J =8.2 Hz, Ar—H) · 1457 6.82(1 H, d, J = 8 Hz, Ar—H) · 6.89(1 H, m, J = 2Hz, Ar— H) · 7.14(1 H, t, J = 8 Hz, Ar—H) · 7.32(2 H, m, Ar—H) · 7.42(1H, m, Ar—H) · 9.25(1 H, br, OH) · 9.43(1 H, br, 108 169.1-174.92.79-2.82(2 H, m, CH2) · DMSO-d6 3469- 332 (M+)- ε max 2548 (λ max2.89(4 H, s, CH2 * 2) · 3368- 241 (Base) 340.6 nm) · 3.01-3.04(2 H, m,CH2) · 1621 6.11(1 H, d, J = 2.1 Hz, Ar— H) · 6.15(1 H, d, J = 2.1 Hz,Ar—H) · 6.97-7.35(8 H, m, Ar—H) · 9.21(1 H, br, OH) · 9.39(1 H, br, OH)· 109 176.7-179.2 2.85-2.89(2 H, m, CH2) · DMSO-d6 3437- 304 ε max21325.6 (λ max 3.13-3.16(2 H, m, CH2) · 3361- (M+, base) 258.0 nm) · εmax 6.15(1 H, d, J = 2 Hz, Ar—H) · 68335.7 (λ max 6.17(1 H, d, J = 2 Hz,Ar—H) 204.6 nm) · 7.21(1 H, d, J = 8 Hz, Ar—H) · 7.39(1 H, t, J = 8 Hz,Ar—H) · 7.48- 7.52(3 H, m, Ar—H) · 7.58(1 H, d, J = 2 Hz, Ar—H) · 7.68(2H, d, J = 8 Hz, Ar—H) · 9.25(1 H, s, OH) · 9.44(1 H, s, OH) · 110194.2-195.6 2.79(2 H, t, J = 6.3 Hz, CH2) · DMSO-d6 3440- pale gray310(M+, ε max 12818 ( λ max 3.02(2 H, t, J = 6.3 Hz, Ar—H) · 3368-needle Base) 282.8 nm) · ε max 6.13(2 H, t, J = 2.8 Hz, Ar—H) · 2923-crystal 35269 (λ max 7.07-7.14(1 H, m, Ar—H) · 2856- 205.2 nm) · 7.26(1H, d, J = 7.8 Hz, Ar—H) · 1623- 7.35-7.38(2 H, m, Ar—H) ·  6987.51-7.54(2 H, m, Ar—H) · 9.21(1 H, s, OH) · 9.4(1 H, s, OH)

TABLE 12 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 111 188.3-191.4 2.83-2.87(2 H, m, CH2) · DMSO-d63369- 310 ε max 22325(λ 3.10-3.13(2 H, m, CH2) · 687- (M+, base) max284.4 nm) · ε max 6.14(1 H, d, J = 2 Hz, 64475(λ max Ar—H) · 6.17(1 H,d, 204.4 nm) J = 2 Hz, Ar—H) · 7.16-7.19(2 H, m, Ar—H) · 7.48- 7.51(2 H,m, Ar—H) · 7.55-7.58(2 H, m, Ar—H) · 9.25(1 H, s, OH) · 9.45(1 H, s,OH)· 112 195.1-197.1 2.33(3 H, s, CH3) · DMSO-d6 3432- pale pink 318(M+,Base) ε max 21032(λ max 2.8(2 H, t, J = 3362- needle 256.4 nm) · ε max6.3 Hz, CH2) · 1625- crystal 56257(λ max 3.09(2 H, t, J = 1612 207.6nm)· 6.3 Hz, CH2) · 6.12(2 H, dd, J = 6.1, 2.4 Hz, Ar—H) · 7.24-7.36(5H, m, Ar—H) · 7.54(2H, d, J = 8.1 Hz, Ar—H) · 9.23(1 H, s, OH) · 9.41(1H, s, OH) 113 151.8-152.7 2.78-2.84(2 H, m, DMSO-d6 3440- 332 (M+)- εmax 4037.3(λ CH2) · 2.88- 3368 241(M⁺⁻ max 275.4 nm) · ε max 2.91(4 H,m, CH2) · 91, base) 69082.7(λ max 3.01-3.04(2 H, m, 206.2 nm) CH2) ·6.10(1 H, d, J = 2 Hz, Ar—H) · 6.14(1 H, d, J = 2 Hz, Ar—H) ·7.01-7.07(2 H, m, Ar—H) · 7.12(1 H, d, J = 2 Hz, Ar—H) · 7.21-7.25(1 H,d, J = 2 Hz, Ar—H) · 7.27-7.28(2 H, d, J = 2 Hz, Ar—H) · 7.31-7.35(2 H,d, J = 2 Hz, Ar—H) · 9.20(1 H, s, OH) · 9.39(1 H, s, OH) 114 163.6-173.92.83-2.86(2H, m, DMSO-d6 3432- 294 ε max 24574.5(λ max CH2) · 3.10-3.153370 (M+, base) 283.0 nm) · ε max (2 H, m, CH2) · 52361.3(λ max 6.13(1H, d, J = 204.8 nm) 2 Hz, Ar—H) · 6.16(1 H, d, J = 2 Hz, Ar—H) · 6.63(1H, m, Ar—H) · 6.91(1 H, d, J = 3 Hz, Ar—H) · 7.19(1 H, d, J = 8 Hz,Ar—H) · 7.55(1 H, dd, J = 8.2 Hz, Ar—H) · 7.63(1 H, d, J = 2 Hz, Ar—H) ·7.77(1 H, s, Ar—H) · 9.25(1 H, s, OH) · 9.45(1 H, s, OH) 115 198.6-201.12.79(2 H, m, CH2) · DMSO-d6 3456- colorless 294(M+, Base) ε max 25034(λmax 3.02(2 H, t, J = 3362- needle 282.2 nm) · ε max 6.3 Hz, CH2) · 2924-crystal 39332(λ max 6.12(2 H, s, Ar—H) · 2856- 207.8 nm) · 6.58(1 H, dd,J = 1622- 3.3, 1.8 Hz, Ar—H) · 874 6.94(1 H, d, J = 3.4 Hz, Ar—H) ·7.26(1 H, t, J = 4.1 Hz, Ar—H) · 7.39-7.41(2 H, m, Ar—H) · 7.72(1 H, d,J = 1.6 Hz, Ar—H) · 9.25(1 H, brs, OH) · 9.43(1H, brs, OH) 116 2.23(3 H,s, CH3) · DMSO-d6 3410- pale pink 318(M+, Base) ε max 23012(λ max 2.82(2H, t, J = 3348- oil 228.2 nm) · ε max 6.3 Hz, Ar—H) · 2923- 22380(λ max3.06(2 H, t, J = 2847- 221.8 nm)· 6.3 Hz, Ar—H) · 1622- 6.10(2 H, dd, J= 751 11.2, 2.3 Hz, Ar—H) · 7.02- 7.29(8 H, m, Ar—H) · 9.22(1 H, s, OH)· 9.43(1 H, s, OH) 117 150.2-152.6 2.81(2 H, t, J = DMSO-d6 3370- palepink 372(M+, Base) ε max 18307(λ max 6.3 Hz, CH2) · 2923- amorphous253.2 nm) · ε max 3.07(2 H, t, J = 2853- 56560(λ max 6.3 Hz, CH2) ·1624- 206.6 nm)· 6.12(1 H, d, J = 1336- 2.4 Hz, Ar—H) · 1174- 6.15(1 H,d, J = 1129 2.4 Hz, Ar—H) · 7.35(1 H, d, J = 7.82 Hz, Ar—H) ·7.45-7.50(2 H, td, Ar—H) · 7.67- 7.73(2 H, m, Ar—H) · 7.96-7.99(2 H, m,Ar—H) · 9.24(1 H, brs, OH) · 9.43(1 H, brs, OH) 118 137.1-143.2 2.81(2H, t, J = DMSO-d6 3445- colorless 338(M+, Base) ε max 20038(λ max 6.3Hz, CH2) · 3370- amorphous 253.2 nm) · ε max 3.05(2 H, t, J = 2922-61114(λ max 6.3 Hz, CH2) · 2855- 207.6 nm)· 6.12(1 H, d, J = 1622- 2.4Hz, Ar—H) · 785 6.15(1 H, d, J = 2.4 Hz, Ar—H) · 7.31(1 H, d, J = 7.8Hz, Ar—H) · 7.4-7.49(4 H, m, Ar—H) · 7.63(1 H, dd, J = 6.4, 1.3 Hz,Ar—H) · 7.72(1 H, t, J = 1.8 Hz, Ar—H) · 9.24(1 H, s, OH) · 9.43(1 H, s,OH) · 119 197.2-199.3 2.85-2.88(2 H, m, DMSO-d6 3371- 319 λ max nm(ε)·CH2) · 3.11-3.14 3224- (M+, base) 307.0(sh, 12300) (2H, m, CH2) · 3059-5.17(2H, br, N— 2885- H2) · 6.14(1 H, 2622- d, J = 2 Hz, 1618- Ar—H) ·6.17(1 H, d, J = 2 Hz, Ar—H) · 6.59(1 H, d, J = 8 Hz, Ar— H) · 6.79(1 H,d, J = 8 Hz, Ar—H) · 6.86(1 H, s, Ar—H) · 7.13(1 H, t, J = 8 Hz, Ar—H) ·7.18(1 H, d, J = 8 Hz, Ar—H) · 7.49(1 H, dd, J = 8.2 Hz, Ar—H) · 7.45(1H, s, Ar—H) · 9.25(1 H, b 120 199.6-201.8 2.87-2.90(2 H, DMSO-d6 3401-349 λ max nm(ε) · m, CH2) · 3.16- 2920- (M+, base)- 260.8(26800) · 323.53.19(2 H, m, CH2) · 1626 322(M⁺− (3500) 6.16(1 H, d, J = 17)- 2 Hz,Ar—H) · 6.18(1 H, d, J = 2 Hz, Ar—H) · 7.28(1 H, d, J = 8 Hz, Ar—H) ·7.64(1 H, dd, J = 8.2 Hz, Ar—H) · 7.72-7.74(1 H, m, Ar—H) · 7.78- 7.82(1H, m, Ar—H) · 8.18(1 H, d, J = 8 Hz, Ar—H) · 8.25(1 H, dd, J = 8.2 Hz,Ar—H) · 8.47(1 H, s, Ar—H) · 9.27(1 H, s, OH) · 9.47( 121 2.88(2 H, t, J= DMSO-d6 3369- λ max nm(ε) · 6 Hz, CH2) · 1624- 204.0(57600) · 261.63.16(2 H, t, J = 1476 (16600) 6 Hz, CH2) · 6.16(1 H, s, Ar—H) · 6.18(1H, d, J = 2 Hz, Ar—H) · 7.26(1 H, d, J = 8 Hz, Ar—H) · 7.51(1 H, dd, J =8.4 Hz, Ar—H) · 7.55(1 H, d, J = 8 Hz, Ar—H) · 7.65(1 H, s, Ar—H) ·8.09(1 H, d, J = 8 Hz, Ar—H) · 8.60(1 H, d, J = 4 Hz, Ar—H) · 8.91(1 H,s, Ar—H) · 9.26(1 H, s, OH) · 9.46(1 H, s, OH) ·

TABLE 13 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 122 211.8-217.3 2.84-2.87(2 H, DMSO-d6 3373- 253 λmax nm(ε) · m, CH2) · 3.09- 2237- (M+, base)- 226.5(sh, 52500) · 3.12(2H, m, CH2) · 1608 236 (M⁺⁻ 281.0(sh, 13900) · 6.15(1 H, d, J = 17) 2 Hz,Ar—H) · 6.19(1 H, d, J = 2 Hz, Ar—H) · 7.34(1 H, d, J = 8 Hz, Ar—H) ·7.72(1 H, dd, J = 8.2 Hz, Ar—H) · 7.80(1 H, s, Ar—H) · 9.33(1 H, s, OH)· 9.55(1 H, s, OH) · 123 196.1-198.5 2.99(2 H, q, J = DMSO-d6 3429- palebrown 326(M+, Base) ε max 27602(λ max 3.8 Hz, CH2) · 3370- amorphous279.6 nm) · ε max 3.23(2 H, q, J = 1609- 54275(λ max 3.9 Hz, CH2) · 692207.6 nm) 6.26(1 H, d, J = 2.4 Hz, Ar—H) · 6.34(1 H, d, J = 2.4 Hz,Ar—H) · 7.12(1H, dd, J = 5.0, 3.6 Hz, Ar—H) · 7.3(1 H, d, J = 8 Hz,Ar—H) · 7.51-7.54(3 H, m, Ar—H) · 7.67(1 H, d, J = 1.9 Hz, Ar—H) ·9.29(1 H, s, OH) · 9.52(1 H, s, OH) 124 148.5-149.6 3.04(2 H, q, J =DMSO-d6 3428- pale orange 310(M+, Base) ε max 22619(λ max 4.1 Hz, CH2) ·3366- amorphous 275.6 nm) · ε max 3.29(2 H, q, J = 1605- 57427(λ max 3.9Hz, CH2) · 829 205.6 nm) 6.31(1 H, d, J = 2.3 Hz, Ar—H) · 6.39(1 H, d, J= 2.4 Hz, Ar—H) · 6.64(1 H, dd, J = 3.6, 1.7 Hz, Ar—H) · 7.03(1 H, d, J= 3.1 Hz, Ar—H) · 7.36(3 H, d, J = 8.0 Hz, Ar—H) · 7.62(1 H, dd, J =7.6, 1.8 Hz, Ar—H) · 7.79(2 H, d, J = 1.7 Hz, Ar—H) · 9.3(1 H, s, OH) ·9.53(1 H, s, OH) 125 175.1-178.3 2.92(2 H, q, J = DMSO-d6 3494- palebrown 320(M+, Base) ε max 24764(λ 3.7 Hz, CH2) · 3462- amorphous max254.4 nm) · ε 3.15(2 H, t, J = 3421- max 64910(λ max 6.2 Hz, CH2) · 1627204.4 nm) 6.26(1 H, s, Ar—H) · 7.19-7.68(8 H, m, Ar—H) · 8.08(1 H, brs,OH) · 8.37(1 H, brs, OH) · 9.06(1 H, brs, OH) 126 207.3-208.13.03-3.06(2 H, DMSO-d6 3435- ε max 21933(λ m, CH2) · 3.33-3.36 3369- max308.0 nm) ·ε (2 H, m, CH2) · 1607 max 61186(λ max 6.30(1 H, d, J = 202.4nm) 2 Hz, Ar—H) · 6.36(1 H, d, J = 2 Hz, Ar— H) · 7.19(1 H, dd, J = 5.3Hz, Ar—H) · 7.47(1 H, d, J = 8 Hz, Ar—H) · 7.50(1 H, d, J = 8 Hz, Ar—H)· 7.57(1 H, d, J = 3 Hz, Ar—H) · 7.61(1 H, d, J = 5 Hz, Ar—H) · 7.62(1H, s, Ar—H) · 9.28(1 H, s, OH) · 9.52(1 H, s, OH) 127 213.7-214.73.02-3.05(2 H, m, DMSO-d6 3447- ε max 26495(λ CH2) · 3.32-3.35 3376- max301.2 nm) · ε (2 H, m, CH2) · 1607- max 55066(λ max 6.30(1 H, d, J =207.6 nm) 2 Hz, Ar—H) · 6.36(1 H, d, J = 2 Hz, Ar—H) · 6.65(1 H, dd, J =3.2 Hz, Ar—H) · 7.01(1 H, d, J = 3 Hz, Ar—H) · 7.49-7.54(1 H, m, Ar—H) ·7.67(1 H, s, Ar—H) · 7.80 (1 H, s, Ar—H) · 9.28(1 H, s, OH) · 9.52(1 H,s, OH) 128 157.6-157.9 0.90(3 H, t, J = DMSO-d6 3353- colorless 298(M+)-ε max 13003(λ max 7 Hz, CH3) · 3170- needle 255(Base) 261.2 nm) · ε1.60(2 H, tq, J = 2964- crystal max 12385(λ 7.7 Hz, CH2) · 1652- max245.6 nm) · ε 2.94(2 H, t, J = 1622- max 53218(λ 7 Hz, CH2) · 2.79(2H,1597 max 206.8 nm) m, CH2) · 3.08(2 H, m, CH2) · 6.07(1 H, d, J = 2 Hz,Ar—H) · 6.11(1 H, d, J = 2 Hz, Ar—H) · 7.18(1 H, d, J = 8 Hz, Ar—H) ·7.78(1 H, dd, J = 2.8 Hz, Ar—H) · 7.83(1 H, d, J = 2 Hz, Ar—H) · 9.23 (1H, br, OH) · 9.43(1 H, br, OH) 129 151.8-152.8 0.90(3 H, t, J = DMSO-d63360- pale pink 314(M+)- ε max 9626(λ max 7 Hz, CH3) · 2959- amorphous271(Base) 315.6 nm) · ε 1.60(2 H, tq, J = 1679- max 5918(λ max 7.7 Hz,CH2) · 1591 276.4 nm) · ε 2.94(2 H, t, J = max 44639(λ 7 Hz, CH2) · 2.99max 208.4 nm) (2 H, m, CH2) · 3.25(2 H, m, CH2) · 6.25(1 H, d, J = 2 Hz,Ar—H) · 6.30(1 H, d, J = 2 Hz, Ar—H) · 7.50(1 H, d, J = 8 Hz, Ar—H) ·7.68(1 H, dd, J = 2.8 Hz, Ar—H) · 7.80(1 H, d, J = 2 Hz, Ar—H) · 9.30(1H, br, OH) · 9.48(1 H, br, OH) 130 119.8-121.7 0.88(3 H, t, J = DMSO-d63367- colorless 312(M+)- ε max 12405(λ max 7 Hz, CH3) · 3203- needle255(Base) 260.0 nm) · ε 1.32(2 H, tq, J = 2946- crystal max 12019(λ 7.7Hz, CH2) · 1656- max 245.6 nm) · ε 1.56(2 H, tt, J = 1597 max 51546(λ7.7 Hz, CH2) · max 206.4 nm) 2.79(2 H, m, CH2) · 2.95(2 H, t, J = 7 Hz,CH2) · 3.06 (2 H, m, CH2) · 6.07(1 H, d, J = 2 Hz, Ar—H) · 6.11(1 H, d,J = 2 Hz, Ar—H) · 7.18(1 H, d, J = 8 Hz, Ar—H) · 7.78(1 H, dd, J = 2.8Hz, Ar—H) · 7.83(1 H, d, J = 2 Hz, Ar—H) · 9.23(1 H, br, OH) · 9.43(1 H131 155.1-158.7 0.88(3 H, t, J = DMSO-d6 3429- pinkish 328(M+)- ε max10260(λ max 7 Hz, CH3) · 3370- white 271(Base) 314.8 nm) · ε 1.31(2 H,tq, J = 2957- amorphous max 6421(λ max 7.7 Hz, CH2) · 1678- 276.8 nm) ·ε 1.56(2 H, tt, J = 1591 max 48033(λ 7.7 Hz, CH2) · max 208.8 nm) 2.94(2H, t, J = 7 Hz, CH2) · 2.99(2 H, m, CH2) · 3.25(2 H, m, CH2) · 6.25(1 H,d, J = 2 Hz, Ar—H) · 6.30(1 H, d, J = 2 Hz, Ar—H) · 7.50(1 H ,d, J = 8Hz, Ar—H) · 7.68(1 H, dd, J = 2.8 Hz, Ar—H) · 7.80(1 H, d, J = 2 Hz,Ar—H) · 9.28(1 H, br, OH) · 9.49(1 H

TABLE 14 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 132 1.38-1.44(5 H, DMSO-d6 3348- oil 354(M+)- ε max9403(λ max m, cyclo-hex) · 2930- 271(Base) 299.2 nm) · ε 1.77-1.83(5 H,m, 2853- max 6935(λ max cyclo-hex) · 3.06(2 H, 1660- 277.6 nm) · ε m,CH2) · 3.32(2 H, 1589 max 47934(λ m, CH2) · 3.34(1 H, max 208.0 nm) m,cyclo-hex) · 6.32(1 H, d, J = 2.4 Hz, Ar—H) · 6.37(1 H, d, J = 2.4 Hz,Ar—H) · 7.58(1 H, d, J = 8.1 Hz, Ar—H) · 7.75 (1 H, dd, J = 1.6, 8.1 Hz,Ar—H) · 7.85(1 H, d, J = 1.6 Hz, Ar—H) · 9.33(1 H, br, OH) · 9.57(1 H,br, O 133 1.17(1 H, m, cyclo- DMSO-d6 3370- oil 338(M+)- ε max 12018(λmax hex) · 1.25- 2931- 255(Base) 261.6 nm) · ε 1.46(4 H, m, cyclo- 2855-max 11355(λ hex) · 1.62- 1661- max 246.0 nm) · ε 1.78(5 H, m, cyolo-1601 max 51180(λ hex) · 2.79(2 H, m, max 206.4 nm) CH2) · 3.06(2 H, m,CH2) · 3.34(1 H, m, cyclo-hex) · 6.07(1 H, d, J = 2 Hz, Ar—H) · 6.11(1H, d, J = 2 Hz, Ar—H) · 7.18 (1 H, d, J = 8 Hz, Ar—H) · 7.78(1 H, dd, J= 2.8 Hz, Ar—H) · 7.82(1 H, d, J = 2 Hz, Ar—H) · 9.23(1 H, br, OH) · 9.4134 141.2-141.7 1.83(1 H, m, cyclo- DMSO-d6 3359- pinkish white 326(M+)-ε max 11180(λ max bu) · 2.07(1 H, m, 2944- amorphous 271(Base) 317.2 nm)· ε cyclo-bu) · 2.20- 1669- max 6902(λ max 2.32(4 H, m, cyclo- 1591277.2 nm) · ε bu) · 3.06(2H, m, max 51325(λ CH2) · max 208.4 nm) 3.32(2H, m, CH2) · 4.15(1 H, dddd, J = 8.5 Hz, each, cyclo-bu) · 6.32(1 H, d,J = 2.5 Hz, Ar—H) · 6.37(1 H, d, J = 2.5 Hz, Ar—H) · 7.58(1 H, d, J = 8Hz, Ar—H) · 7.68(1 H, dd, J = 2.8 Hz, Ar—H) · 7.79(1 H, d, J = 2 Hz,Ar—H) · 9.33(1 H 135 142.2-143.5 1.02(4 H, m, cyclo- DMSO-d6 3371-pinkish white 312(M+, ε max 10456(λ max pro) · 2.85(1 H, 1660- amorphousBase)-271 317.6 nm) · ε m, cyclo-pro) · 1591 max 6176(λ max 3.00(2 H, m,CH2) · 277.2 nm) · ε 3.27(2 H, m, CH2) · max 47193(λ 6.26(1 H, d, J =max 208.8 nm) 3 Hz, Ar—H) · 6.31(1 H, d, J = 3 Hz, Ar—H) · 7.53(1 H, d,J = 8 Hz, Ar—H) · 7.75(1 H, dd, J = 2.8 Hz, Ar—H) · 7.88(1 H, d, J = 2Hz, Ar—H) · 9.26(1 H, brs, OH) · 9.51(1 H, brs, OH) 136 1.07(6 H, d, J =DMSO-d6 3332- oil 314(M+)- ε max 8618(λ max 6.8 Hz, CH3*2) · 2972-271(Base) 316.0 nm) · ε 3.00(2 H, m, CH2) · 1664- max 5596(λ max 3.26(2H, m, CH2) · 1589 276.8 nm) · ε 3.59(1 H, q, J = max 41069(λ 6.8 Hz, CH)· max 208.4 nm) 6.25(1 H, d, J = 2.4 Hz, Ar—H) · 6.30(1 H, d, J = 2.4Hz, Ar—H) · 7.50(1 H, d, J = 8.1 Hz, Ar—H) · 7.69(1 H, dd, J = 1.6, 8.1Hz, Ar—H) · 7.79(1 H, d, J = 1.6 Hz, Ar—H) · 9.26(1 H, br, OH) · 9.50(1H, br, OH) 137 151.7-153.7 1.29(9 H, s, CH3*3) · CDCI3 3373- pinkishwhite 300(M+, ε max 10084(λ max 3.11(2 H, m, CH2) · 2963- amorphousBase)-285 274.4 nm) · ε 3.39(2 H, m, CH2) · 1604 max 7945(λ max 3.34(1H, m, cyclo- 261.2 nm) · ε hex) · max 46454(λ 4.8(1 H, br, OH) · max204.0 nm) 4.9(1 H, br, OH) · 6.19(1 H, d, J = 2 Hz, Ar—H) · 6.54(1 H, d,J = 2 Hz, Ar—H) · 7.15(1 H, dd, J = 2.8 Hz, Ar—H) · 7.22(1 H, d, J = 8Hz, Ar—H · 7.38(1 H, d, J = 2 Hz, Ar—H)· 138 176.7-177.6 2.13(3 H, s,CH3) · DMSO-d6 3461- pale pink plate 315(M+, Base)- ε max 16817(λ max2.95(2 H, m, CH2) · 3370- crystal 300-284 296.0 nm) · ε 3.23(2 H, m,CH2) · 1607 max 13182(λ 3.90(3 H, s, CH3) · max 6.23(1 H, d, J = 274.8nm) · ε 2.4 Hz, Ar—H) · max 50814(λ 6.28(1 H, d, J = max 210.4 nm) 2.4Hz, Ar—H) · 7.40(2 H, m, Ar—H) · 7.52(1 H, m, Ar—H) · 9.20(1 H, br, OH)· 9.43(1 H, br, OH)· 139 110.7-112.4 1.30-1.33(3 H, m, DMSO-d6 3452-colorless 329(M+, base)- ε max 14745.1(λ CH3) · 3.01-3.04 3371-amorphous 284 max 296.4 nm) · ε (2 H, m, CH2) · 2938- max 14631.9(λ max3.30-3.32(2 H, m, 1607 258.0 nm) CH2) · 4.20-4.26(2 H, m, CH2) · 6.32(1H, d, J = 2.4 Hz, Ar—H) · 6.35(1 H, d, J = 2.4 Hz, Ar—H) · 7.48(2 H, m,Ar—H) · 7.59(1 H, m, Ar—H) · 9.2(1 H, br, OH) · 9.5(1 H, br, OH) · 1403.00-3.04(2 H, m, DMSO-d6 3276- colorless TMS ε max 16018(λ max CH2) ·3.14-3.18, 2924- amorphous 447(M⁺ 1) 256.4 nm) · ε 3.45-3.47(2 H, m,1674- max 14603(λ CH2) · 6.41(1 H, d, 1611- max J = 2.4 Hz, Ar—H) · 1057244.8 nm) · ε 6.68(1 H, d, J = max 45362(λ 2.4 Hz, Ar—H) · max 206.4 nm)7.79(1H, d, J = 8.1 Hz, Ar—H) · 7.94(1 H, dd, J = 1.5 Hz, Ar—H) · 8.02(1H, dd, J = 1.5, 8.1 Hz, Ar—H) · 9.63(1 H, s, OH) · 9.83(1 H, s, OH) 1412.87-2.90(2 H, t, DMSO-d6 3366- white λ max nm(ε) · J = 6 Hz, CH2) ·2924- 268.2(11100) · 253.2 3.13-3.16(2 H, t, 1626- (12400) J = 6 Hz,CH2) · 1599- 6.17(1 H, d, J = 2 Hz, Ar—H) · 6.20(1 H, d, J = 2 Hz, Ar—H)· 7.31(1 H, d, J = 8 Hz, Ar—H) · 7.59-7.64(3H, m, Ar—H) · 7.71-7.74 (2H,m, Ar—H) · 7.78(2 H, d, J = 7 Hz, Ar—H) · 9.31(1 H, s, OH) · 9.51(1 H,s, OH) 142 1.09(3 H, t, J = DMSO-d6 3369- 316 λ max nm(ε) · 7 Hz, CH3) ·2.52(3 H, 2966- (M+, base)- 2052(31900)·218.8 s, SCH3) · 2.70- 2923-301(M +− (32000) · 271.6 2.85(1 H, m, CH2) · 2872- 15) · 283 (29000)6.71(1 H, s, Ar—H) · 1595- (M +− 33) · 269 6.85(1 H, s, Ar— 1575- (M +−47) H) · 6.93(1 H, s, 1501- Ar—H) · 7.23(1 H, 1458 d, J = 8 Hz, Ar—H) ·7.33(1 H, s, Ar—H) · 7.44(1 H, d, J = 8 Hz, Ar—H) ·? (1 H, ?, OH) ·? (1H, ?, OH)·

TABLE 15 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 143  37.9-41.5 1.15(3 H, t, J = CDCI3 3499- orange270(M+, Base) ε max 36839(λ max 7.6 Hz, CH3) · 3262- needle 219.2 nm)·2.75(2 H, br, CH2) · 1588 crystal 5.25(2 H, s, OH) · 6.73(1 H, s, Ar—H)6.88(1 H, s, Ar—H) · 7.00(1 H, s, Ar—H) · 7.21-7.29(2 H, m, Ar—H) ·7.37(1 H, d, J = 7.5 Hz, Ar—H) · 7.51(1 H, d, J = 7.1 Hz, Ar—H) 1440.99(3 H, t, J = CDCI3 3379- orange 272(M+, Base) ε max 8392(λ 7.2 Hz,CH3) · 2962- oil max 273.6 nm) · ε 1.62-1.73(2 H, 2932- max 45531(λ maxm, CH2) · 3.08(1 H, 2873- 205.2 nm) · dd, J = 14.8, 1598- 10.3 Hz, CH2)· 1504 3.25(1 H, dd, J = 14.8, 3.6 Hz, CH2) · 3.42(1 H, m, CH) · 5.24(1H, brs, OH) · 5.32(1 H, brs, OH) · 6.71(1 H, s, Ar—H) 6.98(1 H, s, Ar—H)· 7.04(1 H, t, J = 7.2 Hz, Ar—H) · 7.12(1 H, d, J = 7.13 Hz, Ar—H) ·7.17(1 H, t, J = 7.6 145  68.2-70.1 2.40(3 H, s, CH3) · CDCI3 3393-orange 256(M+, Base) ε max 19345(λ max 5.31(1 H, s, OH) · 3216- needle265.6 nm) · ε max 6.71(1 H, s, Ar—H) · 1589 crystal 39937(λ max 6.92(1H, s, Ar—H) · 219.2 nm)· 7.00(1 H, s, Ar—H) · 7.24-7.29(3 H, m, Ar—H) ·7.38(1 H, d, J = 1.5 Hz, Ar—H) · 7.50(1 H, d, J = Hz, Ar—H) · 146 (3 H,t, J = CDCI3 3369- pale yellow 258(M+, Base) λ max nm(ε) · Hz, CH3) ·2.98(1 H, 2962- oil 206.0(47400)-273.2 dd, J = 14.8, 2927- (8700) 9.8Hz, CH2) · 1598- 3.39(1 H, dd, J = 1506- 14.8, 3.9 Hz, CH2) · 1472 (1 H,q, CH) · 5.12(1 H, s, OH) · 5.24(1 H, s, OH) · 6.70(1 H, s, Ar—H) 7.00(1H, s, Ar—H) · 7.02-7.06(1 H, m, Ar—H) · 7.16(2 H, s, Ar—H) · 7.40(1 H,d, J = 7.6 Hz, Ar—H) 147 1.16(3 H, t, J = CDCI3 3213- pale red 254(M+,Base) λ max nm(ε) · 7.6 Hz, CH3) · 2962- oil 212.0(40800) · sh 2.77(2 H,d, J = 2926- 230(27300) · 263.6 6.6 Hz, CH2) · 2869- (20200) · 292.8(sh4.74(1 H, s, OH) · 1593 7000) 6.72(1 H, dd, J = 8.4, 2.4 Hz, CH) ·6.94(1 H, s, Ar—H) · 6.98(1 H, d, J = 2.3 Hz, Ar—H) · 7.09(1 H, d, J =8.4 Hz, Ar—H) 7.23(1 H, dd, J = 7.2, 0.9 Hz, Ar—H) · 7.29(1 H, td, J =7.1, 1.2 Hz, Ar—H) · 738(1 H, d, J = 7.7 Hz, Ar—H) · 7.52(1 H, dd, 1480.99(3 H, t, J = CDCI3 3360- colorless 256(M+)-213 λ max nm(ε) · 7.4 Hz,CH3) · 1.59- 2962- oil (Base) 203.6(31900) · 274.0 1.77(2 H, m, CH2) ·2931- (6800) 3.06(1 H, dd, J = 2873- 15.2, 10.2 Hz, CH2) · 1601- 3.29(1H, dd, J = 1493 15.2, 3.2 Hz, CH2) · 3.47(1 H, q, CH) · 4.62(1 H, s, OH)· 6.63(1 H, dd, J = 8.2, 2.6 Hz, Ar—H) · 6.94(1 H, d, J = 2.5 Hz, Ar—H)· 7.01(1 H, d, J = 8.3 Hz, Ar—H) · 7.07(1 H, td, J = 7.8, 7.8 Hz, Ar—H)7.15(1 H, d, J = 149 2.40(3 H, s, CH3) · COCI3 3369- redoil 240(M+,Base) ε max 17324(λ max 4.86(1 H, s, OH) · 1598- 264.4 nm) · ε max6.71(1 H, dd, J = 1489- 35918(λ max 8.4, 2.5 Hz, Ar—H) · 1473 208.0 nm)6.98(2 H, s, Ar—H) · 7.07(1 H, d, J = 8.4 Hz, Ar—H) · 7.23-7.31(2 H, m,Ar—H) · 7.4(1 H, dd, J = 7.7, 1.0 Hz, Ar—H) · 7.51(1 H, dd, J = 7.5, 0.9Hz, Ar—H) · 150 1.06(6 H, t, J = CDCI3 3491- 300(M+, ε max 19832(λ max7.5 Hz, CH3) · 3308- Base)- 266.8 nm) · ε max 2.51-2.56(1 H, 2978- 285-28582(λ max m, CH2) 2969- 267-254 239.6 nm) · ε max 3.31-3.15(1 H, 2933-44022(λ max m, CH2)5.39(2H, 2871- 206.0 nm)· brs, OH) · 2834- 6.99(1 H,s, Ar—H) 1608- 7.03(1 H, s, Ar—H) · 1584- 7.15-7.16(1 H, m, 1503- Ar—H)· 7.24- 7.26(1 H, m, Ar—H) · 7.37-7.38(1 H, m, Ar—H) · 7.47-7.48 (1 H,m, Ar—H)· 151 1.29(3 H, d, J = CDCI3 3361- colorless λ max nm(ε) · 7.0Hz, CH3) · 2962- oil 205.6(36500) · 272.4 2.98(1 H, dd, J = 2927- (8300)15.1, 9.9 Hz, CH2) · 2874- 3.38(1 H, dd, J = 1601- 15.1, 3.2 Hz, CH2) ·1494 3.72-3.78(1 H, m, CH) · 4.7(1 H, s, OH) · 6.64(1 H, dd, J = 8.4,2.6 Hz, Ar—H) · 6.96(1 H, d, J = 2.5 Hz, Ar—H) · 7(1 H, d, J = 8.3 Hz,Ar—H) · 7.05-7.10(1 H, m, Ar—H) · 7.19(2 H, d, J = 30 Hz, Ar—H) · 7.43(1H, d, J = 7.7 Hz, Ar—H) 152 0.98(3 H, t, J = CDCI3 + C 3372- 7.6 Hz,CH3) · 1.34- D3OD 3270- 1.42(2 H, m, CH2) · 2959- 1.95-2.05(1 H, m,2937- CH2) · 2.43-2.48 2873- (1 H, m, CH2) · 1647- 4.82(1 H, t, J =1595- 8 Hz, CH) · 7.06(1 H, 1582- s, Ar—H) · 1506- 7.14(1 H, t, J = 14628 Hz, Ar—H) · 7.33- 7.40(2H, m, Ar—H) · 7.58(1 H, s, Ar—H) · 7.65(1 H,d, J = 7.6 Hz, Ar—H) · 153 242.9-248.4 0.91(3 H, t, J = DMSO-d6 3504-orange 352(M+, λ max nm(ε) · 7.2 Hz, CH3) · 1.92- 3288- needle Base)-205.2(28400) · 244.4 2.01(1 H, m, CH2) · 2968- crystal 323 (24400)-260.02.33-2.43(1 H, m, 2935- (22500) · 280.4 CH2) · 4.61-4.65 2877- (21200) ·328.8(sh (1 H, m, CH) · 1645- 7500) 6.59-6.60(1 H, m, 1596- Furyl-H) ·6.98(1 H, 1503- s, Ar—H) · 1465 7.04(1 H, d, J = 3.3 Hz, Furyl-H) ·7.39(1 H, d, J = 8.2 Hz, Ar—H) · 7.50(1 H, s, Ar—H) · 7.77(2 H, m, Ar—H,Furyl-H) · 8.01(1 H, s Ar—H) ·

TABLE 16 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 154 274.3-276.1 0.99(3 H, t, J = DMSO-d6 3480- orange362(M+, Base) λ max nm(ε) · 7.2 Hz, CH3) · 2.01- 3343- amorphous204.4(54900) · 246.4 2.08(1 H, m, CH2) · 1645- (37300) · 260.82.39-2.51(1 H, 1600- (40400) · 3324 m, CH2) · 1508 (6200) 4.72(1 H, t, J= 7.0 Hz, CH) · 7.04 (1 H, s, Ar—H) · 7.44(1 H, t, J = 7.2 Hz, Ar—H) ·7.5 K3H, q, J = 7.6 Hz, Ar—H) · 7.57(1 H, s, Ar—H) · 7.73(2 H, d, J =7.5 Hz, Ar—H) · 7.81(1 H, dd, J = 8.1, 1.4 Hz, Ar—H) · 8.02(1 H, d, J =1.4 Hz, Ar—H) · 155 270.3-271.9 0.98(3 H, t, J = DMSO-d6 3509- needle368(M+, λ max nm(ε) · 7.2 Hz, CH3) · 1.98- 3282- crystal Base)-205.6(30200) · 246.4 2.05(1 H, m, CH2) · 2974- 335- (28900) · 260(sh2.41-2.49(1 H, 2934- 24700) · 285.2(25800) m, CH2) · 4.69(1 H, 2875- t,J = 7.1 Hz, 1645- CH) · 7.04(1 H, s, 1597- Ar—H) · 1506 7.2(1 H, dd, J =4.7, 4.0 Hz, Ar—H) · 7.43(1 H, d, J = 8.2 Hz, Ar—H) · 7.57(1 H, s, Ar—H)· 7.63(2 H, dd, J = 2.6, 2.5 Hz, Ar—H) · 7.78(1 H, dd, J = 8.1, 1.5 Hz,Ar—H) · 8.02(1 H, d, J = 1.6 Hz, Ar—H) · ·· 156 109.7-111.9 1.03(3 H, t,J = CDCI3 3325- pale yellow 430(M+, base) λ max nm(ε) · 7.2 Hz, CH3) ·2.08- 2970- needle 334.8(4800) · 260.4 2.15(1 H, m, CH2) · 2939- crystal(36100) · 248.4(sh 2.49-2.56(1 H, m, 2879- 31600) · 205.6(43800) CH2) ·4.79(1 H, t, 1649- J = 7.2 Hz, CH) · 1602- 6.03(1 H, s, OH) · 1507-7.16(1 H, s, Ar—H) · 1336 7.22(1 H, s, OH) · 7.42(1 H, d, J = 8.1 Hz,Ar—H) · 7.54(1 H, t, J = 7.8 Hz, Ar—H) · 7.60-7.62(2 H, m, Ar—H) ·7.71(1 H, d, J = 7.6 Hz, Ar—H) · 7.78(1H, s, CH) · 7.91(1 H, d, J = 1.5Hz, A 157 175.5-176.8 1.03(3 H, t, J = CDCI3 3494- pale yellow 396 (M+,λ max nm(ε) · 7.5 Hz, CH3) · 2.07- 3302- amorphous Base)- 334.4(6200) ·260.8 2.14(1 H, m, CH2) · 2967- 363- (41000) · 246.4(sh 2.49-2.56(1H, m,2936- 35500) · 209.2(49700) CH2) · 4.77(1 H, t, 2877- J = 6.8 Hz, CH) ·1646- 7.14(1 H, s, Ar—H) · 1595- 7.31-7.42(4 H, m, 1581- Ar—H) · 7.52(1H, 1508- s, Ar—H) · 758(1 H, 1466 d, J = 8.1 Hz, Ar—H) · 7.87(1 H, d, J= 1.6 Hz, Ar—H) · 7.95(1 H, s, Ar—H) · 158 179.2-181.1 1.00(3 H, t, J =DMSO-d6 3511- dark red 376(M+, λ max nm(ε) · 7.2 Hz, CH3) · 2.00- 3293-amorphous Base) 337.2(5300) · 290 2.07(1 H, m, CH2) · 2970- (sh 11200) ·258.4 2.26(3 H, s, Ar—CH3) · 2935- (31000) · 244.4 2.46- 2877- (32500) ·207.6(46600) 2.54(1 H, m, CH2) · 1645- 4.68-4.72(1 H, m, 1599- CH) ·7.03(1 H, s, 1507- Ar—H) · 7.24- 1455 7.34(4H, m, Ar—H) · 7.46(1 H, d, J= 8.1 Hz, Ar—H) · 7.51(1 H, dd, J = 8.1, 1.2 Hz, Ar—H) · 7.58(1 H, s,Ar— H) · 7.70(1 H, d, J = 1.2 Hz, CH) · 9.65(1 H, s, OH) · 10.26(1 H, s,OH 159 238.7-241.7 3.04(2 H, q, J = DMSO-d6 3478- 352 λ max nm(ε) · 4.1Hz, CH2) · 3430- (M+, Base), 301.6(33200) · 286 3.29(2 H, q, J = 2974-295- (sh 31400) · 239.6 3.9 Hz, CH2) · 1644- 319- (25800) · 204.4(33600)6.31(1 H, d, J = 1600- 2.3 Hz, Ar—H) · 1500 6.39(1 H, d, J = 2.4 Hz,Ar—H) · 6.64(1 H, dd, J = 3.6, 1.7 Hz, Ar—H) · 7.03(1 H, d, J = 3.1 Hz,Ar—H) · 7.36(3 H, d, J = 8.0 Hz, Ar—H) · 7.62(1 H, dd, J = 7.6, 1.8 Hz,Ar—H) · 7.79(2 H, d, J = 1.7 Hz, Ar—H) · 9.3(1 H, s, OH) · 9.53(1 H, s,OH) 160 271.9-273.3 0.99(3 H, t, J = DMSO-d6 3494- orange 376(M+, λ maxnm(ε) · 7.2 Hz, CH3) · 2.02- 3315- needle Base) 262.4(40933) · 245.62.05(1 H, m, CH2) · 2970- crystal (37746) · 204.4(63180) 2.39(3 H, s,CH3) · 2878- 2.45-2.48(1 H, m, 1645- CH2) · 4.70(1 H, t, 1599- J = 7.2Hz, CH) · 1505 7.04(1 H, s Ar—H) · 7.32(2 H, d, J = 7.9 Hz, Ar—H) ·7.46(1 H, d, J = 8.2 Hz, Ar—H) · 7.57(1 H, s, Ar—H) · 7.63(2 H, d, J =8.0 Hz, Ar—H) · 7.79(1 H, d, J = 8.0 Hz, Ar—H) · 7.99(1 H, d, J = 1.0Hz, Ar—H) · 9.9 161 277.4-279.2 0.94(3 H, t, J = DMSO-d6 3509- needle402 λ max nm(ε) · 336 7.4 Hz, CH3) · 3288- crystal (M+, Base) (sh 33900)· 318.8 2.04(2 H, m, CH2) · 2965- (46200) · 241.2 4.66(1 H, t, J = 2874-(30200) · 207.6(46100) 6.0 Hz, CH) · 1647- 6.97(1 H, s, Ar—H) · 1597-7.27-7.34(2 H, m, 1506- Ar—H) · 7.51(1 H, 1450 s, Ar—H) · 7.61-7.67(3 H,m, Ar—H) · 7.78- 7.82(3 H, m, Ar—H) · 9.62(1 H, brs, OH) · 10.09(1 H,brs, OH) 162 225.7-227.4 3507- needle λ max nm(ε) 3282- crystal 1645-1598- 1583- 1502 163 225.7-227.3 needle λ max nm(ε) crystal

TABLE 17 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 166 0.90(3 H, t, J = DMSO-d6 ε max 6269(λ max 7.2 Hz,CH3) · 1.91- 338.8 nm) · ε max 1.97(1 H, m, CH2) · 23173(λ max2.35-2.41(1 H, 257.6 nm) · ε max m, CH2) · 4.61(1 H, 23680(λ max t, J =7.2 Hz, 243.6 nm) · CH) · 6.96(1 H, s, Ar—H) · 7.23(1 H, t, J = 7.6 Hz,Ar—H) · 7.35(1 H, d, J = 7.7 Hz, Ar—H) · 7.45- 7.49(2 H, m, Ar—H) ·7.70(1 H, d, J = 7.6 Hz, Ar—H) 167 0.90(3 H, t, J = DMSO-d6 ε max 6426(λmax 7.2 Hz, CH3) · 1.92- 339.2 nm) · ε max 1.95(1 H, m, CH2) · 23731(λmax 2.36-2.41(1 H, 257.6 nm) · ε max m, CH2) · 4.61(1 H, 24247(λ max t,J = 7.2 Hz, 243.6 nm)· CH) · 6.96(1 H, s, Ar—H) · 7.23(1 H, t, J = 7.2Hz, Ar—H) · 7.35(1 H, d, J = 7.7 Hz, Ar—H) · 7.45- 7.49(2 H, m, Ar—H) ·7.70(1 H, d, J = 7.6 Hz, Ar—H) · 168 293.2(decom- 0.99(3 H, t, J =DMSO-d6 pale yellow 402(M+, λ max nm(ε) · position) 7.2 Hz, CH3) · 2.01-amorphous Base) 310.4(32461) · 245.6 2.08(1 H, m, CH2) · (31228) ·206.4(48450) 2.45-2.2, 52(1 H, m, CH2) · 4.75(1 H, t J = 7.2 Hz, CH) ·7.07(1 H, s, Ar—H) · 7.33(1 H, t, J = 7.6 Hz, ) · 7.40(1 H, t, J = 7.6Hz, ) · 7.54(1 H, d, J = 8.3 Hz, Ar—H) · 7.58(1 H, s, Ar—H) · 7.59(1 H,s, Ar—H) · 7.69(1 H, d, J = 8.2 Hz, Ar—H) · 7.72(1 H, d, J = 7.6 Hz,Ar—H) · 8.05(1 H, 169 216.8-219.1 0.99(3 H, t, J = DMSO-d6 pale brown446(M+, λ max nm(ε) · 7.4 Hz, CH3) · 2.01- needle Base) 260.4(36913) ·245.2 2.08(1 H, m, CH2) · crystal (35410) · 204.0(59710) 2.39-2.51(1 H,m, CH2) · 4.72(1 H, t, J = 7.2 Hz, CH) · 7.05(1 H, s, Ar—H) ·7.49-7.51(3 H, m, Ar—H) · 7.57(1 H, s, Ar—H) · 7.82-7.84(1 H, m, Ar—H) ·7.86-7.88 (2 H, m, Ar—H) · 8.06(1 H, s, Ar—H) · 10.04(2 H, brs, OH)170 >312(decom- 0.99(3 H, t, J = DMSO-d6 brown 446(M+, λ max nm(ε) ·position) 7.2 Hz, CH3) · 2.01- amorphous Base) 302.8(21641)·209.6 2.08(1H, m, CH2) · (44871) 2.44-2.51(1 H, m, CH2) · 4.73(1 H, t, J = 7.2 Hz,CH) · 7.07 (1 H, s, Ar—H) · 7.41-7.52(3 H, m, Ar—H) · 7.58(1 H, s, Ar—H)· 7.90(2 H, d, J = 7.9 Hz, Ar—H) · 8.01-8.05(2 H, m, Ar—H) · 8.16(1 H,s, Ar—H) · 9.68(1 H, s, OH) · 10.30(1 H, s, OH) 171 >300 1.0(3 H, t, J =DMSO-d6 pinkish-white 438(M+, λ max nm(ε) · 6.8 Hz, CH3) · 2.04-amorphous Base) 279.6(33361) · 245.6 2.07(1 H, m, CH2) · (25555) ·205.6(59442) 2.45-2.52(1 H, m, CH2) · 4.73(1 H, t, J = 7.2 Hz, CH) ·7.06(1 H, s, Ar—H) · 7.42-7.56(4 H, m, Ar—H) · 7.58(1 H, s, Ar—H) ·7.77-7.89(7 H, m, Ar—H) · 8.09(1 H, s, Ar—H) 172 251.4- 0.94(3 H, t, J =DMSO-d6 pinkish-white 418(M+, λ max nm(ε) · 255.5(decom- 7.2 Hz, CH3) ·1.98- amorphous Base)- 233.2(38900) · 250.0 position) 2.07(2 H, m, CH2)· 361-385 (33300) · 312.0 4.66(1 H, t, J = (29900) · 340.0(21700) 7.1Hz, CH) · 6.96(1 H, s, Ar—H) · 7.35-7.40(2 H, m, Ar—H) · 7.51(1 H, s,Ar—H) · 7.60- 7.66(2 H, m, Ar—H) · 7.77(1 H, d, J = 8 Hz, Ar—H) · 7.85(1H, d, J = 8 Hz, Ar—H) · 7.97-8.01(2 H, m, Ar—H) · 9.68(1 H, s, OH) ·10.30(1 H, s, OH) 173 0.92(3 H, t, J = DMSO-d6 pale brown oil 394(M+,7.2 Hz, CH3) · 1.94- Base) 1.99(1 H, m, CH2) · 2.37-2.41(1 H, m, CH2) ·4.61(1 H, t, J = 7.1 Hz, CH) · 6.79(1 H, d, J = 8.1 Hz, Ar—H) · 6.94(1H,dd, J = 8.1, 1.8 Hz, Ar—H) · 6.98(1 H, s, Ar— H) · 7.01(1 H, d, J = 1.8Hz, Ar—H) · 7.35(1 H, d, J = 8.1 Hz, Ar—H) · 7.50(1 H, s, Ar—H) · 7.60(1H, dd, J = 8.1, 1.3 Hz, Ar—H) · 7.79(1 H, 174 0.92(3 H, t, J = DMSO-d6pale orange 394(M+, 7.2 Hz, CH3) · 1.94— oil Base) 1.99(1 H, m, CH2) ·2.35-2.42(1 H, m, CH2) · 4.60(1 H, t, J = 7.2 Hz, CH) · 6.29(1 H, dd, J= 8.4, 2.0 Hz, Ar—H) · 6.39(1 H, d, J = 2.0 Hz, Ar—H) · 6.96(1 H, s,Ar—H) · 7.06(1 H, d, J = 8.3 Hz, Ar—H) · 7.30(1 H, d, J = 8.1 Hz, Ar—H)· 7.50(1 H, s, Ar—H) · 7.56(1 H, d, J = 8.1 Hz, Ar—H) · 7.79(1 H, s, Ar—175 221.8-225.0 0.94(3 H, t, J = DMSO-d6 yellow 407(M+, λ max nm(ε) ·7.2 Hz, CH3) · 1.98- needle Base) 260.4(52815) · 2.01(1 H, m, CH2) ·crystal 2.39-2.47(1 H, m, CH2) · 4.69(1 H, t, J = 7.2 Hz, CH) · 7.01(1H, s, Ar—H) · 7.48(1 H, d, J = 8.2 Hz, Ar—H) · 7.53(1 H, s, Ar—H) ·7.75(1 H, t, J = 8 Hz, Ar—H) · 7.87(1 H, dd, J = 8.1, 9 Hz, Ar—H) ·8.11(1 H, d, J = 1.9 Hz, Ar—H) · 8.16(1 H, d, J = 7.7 Hz, Ar—H) ·8.21-8.23(1 H, m, Ar 176 245.5-246.4 0.93(3 H, t, J = DMSO-d6pinkish-white 377(M+, λ max nm(ε) · 7.2 Hz, CH3) · 1.95- amorphous Base)243.2(43705) · 206.4 1.99(1H, m, CH2) · (49928) 2.39-2.42(1 H, m, CH2) ·4.62- 4.65(1 H, m, CH) · 5.15(2 H, s, NH2) · 6.56(1 H, dd, J = 7.9, 1.6Hz, Ar—H) · 6.77(1 H, d, J = 7.8 Hz, Ar—H) · 6.84(1 H, d, J = 1.6 Hz,Ar—H) · 6.98(1 H, s, Ar—H) · 7.08(1 H, dd, J = 7.9, 7.8 Hz, Ar—H) ·7.39(1 H, d, J = 8.2 Hz, Ar—H) · 7.51(1 H, s, Ar

TABLE 18 Example melting point NMR No (centi degree) NMR solvent IRAppearance Mass UV 177 155.4-159.4 0.93(3 H, t, J = DMSO-d6pinkish-white 378(M+, 7.2 Hz, CH3) · 1.95- needle Base) 1.99(1 H, m,CH2) · crystal 2.38-2.41(1 H, m, CH2) · 4.60- 4.64(1 H, m, CH) · 6.83(2H, d, J = 9.3 Hz, Ar—H) · 6.70(1 H, s, Ar—H) · 7.36(1 H, d, J = 8.2 Hz,Ar—H) · 7.50(3 H, d, J = 9.3 Hz, Ar—H) · 7.66(1 H, dd, J = 8.2, 1.9 Hz,Ar—H) · 7.86(1 H, d, J = 1.9 Hz, Ar—H) · 178 1.00(3 H, t, J = CDCI3colorless 300(M+, 7.2 Hz, CH3) · 2.03- needle Base)- 2.06(1 H, m, CH2) ·crystal 285 2.53-2.57(1 H, m, CH2) · 3.97(3 H, s, OCH3) · 4.71-4.74(1 H,m, CH) · 5.54(1 H, s, OH) · 7.01(1 H, s, Ar—H) · 7.13-7.16(1 H, m, Ar—H)· 7.34- 7.41(2 H, m, Ar—H) · 7.65(1 H, d, J = 7.6 Hz, Ar—H) · 7.76(1 H,s, Ar—H) · - 179 1.01(3 H, t, J = CDCI3 pale orange 300(M+, 7.2 Hz, CH3)· 202- needle Base)- 2.09(1 H, m, CH2) · crystal 285 2.51-2.58(1 H, m,CH2) · 3.89(3 H, s, OCH3) · 4.70-4.73(1 H, m, CH) · 6.08(1 H, s, OH) ·7.12(1 H, s, Ar—H) · 7.14- 7.16(1 H, m, Ar—H) · 7.33-7.41(2H, m, Ar—H) ·7.65(1 H, d, J = 7.7 Hz, Ar—H) · 7.71(1 H, s, Ar—H)· 180 0.90(3 H, t, J= DMSO-d6 UV I max: 7.3 Hz, CH3) · 244 nm(e 25,100), 1.97(1 H, m,272(12,700), 337 CH2CH3) · 2.42(1 H, (4,000) m, CH2CH3). 3.3-3.5 (7 H,m, Glu-H) · 4.03(1 H, m, Glu-H), 4.61(1 H, m, 11-H) · 5.29(0.5 H, d, J =7.3 Hz, anomeric) · 5.18(0.5 H, d, J = 7.3 Hz, anomeric) · 7.2-7.8(6 H,m, aromatic)

Example 164

Preparation of11-Ethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 4)

Synthesis of Carboxylic Acid (67)

A mixture of 39.3 g (F.W. 154.19, 255 mmol) of thiosalicylic acid (65),55.4 g (F.W. 217.06, 255 mmol) of 4-bromoveratrole, 1.90 g (F.W. 63.55,30.0 mmol) of copper (powder), 5.7 g (F.W. 190.45, 30.0 mmol) of copper(I) iodide, 45.0 g (F.W. 138.21, 326 mmol) of potassium carbonate and120 mL of N-methyl-2-pyrrolidone was stirred at 150° C. for four hours.After the reaction, the reaction solution was cooled by standing to 70to 80° C., and ice water was added thereto and the resulting solutionwas made pH 2 with hydrochloric acid. The deposited crude crystals werecollected by filtration, washed with water, diisopropyl ether and hexanein the order named and dried to obtain 74.4 g of a crude product. Thisproduct was recrystallized from 1,4-dioxane to obtain 55 g of carboxylicacid (67). Ethyl acetate was added to the crude carboxylic acid obtainedby concentrating the mother liquor, and the resulting solution wasfiltered and then, the residue was washed with ethyl acetate to obtain6.1 g (total yield 83%) of carboxylic acid (67).

Synthesis of Alcohol (68)

To a solution of 75.2 g (F.W. 290.34, 259 mmol) of carboxylic acid (67)in 200 mL of tetrahydrofuran, 10.4 g (F.W. 37.83, 274 mmol) of sodiumborohydride was added at 0° C. and then, 37.0 mL (F.W. 141.93, d=1.154,301 mmol) of boron trifluoride diethyl etherate was added dropwisethereto at the same temperature, and the resulting solution was stirredat room temperature for one hour. To this reaction solution was slowlyadded ice water and the resulting solution was extracted with ethylacetate and the extract was washed with water and then with a saturatedsodium chloride aqueous solution. The obtained reaction solution wasdried with anhydrous magnesium sulfate and then, the solvent was removedunder reduced pressure to obtain 73.4 g of crude alcohol (68).

Synthesis of Bromide (69)

To a solution of 73.4 g (F.W. 276.36) of crude alcohol (68) in 100 mL ofmethylene chloride, 8.5 mL (F.W. 270.70, d=2.850, 89.0 mmol) ofphosphorus tribromide was added at 0° C. After stirring at roomtemperature for 30 minutes, this reaction solution was added ontocrushed ice. The solution was further stirred at room temperature for 30minutes and then, water was added thereto and the resulting solution wasextracted with methylene chloride and the extract was washed with waterand a saturated sodium chloride aqueous solution. The obtained solutionwas dried with anhydrous magnesium sulfate and then, the solvent wasremoved under reduced pressure. As the result, 83.4 g of a crude productwas obtained. This crude bromide was recrystallized from methylenechloride-hexane to obtain 75.2 g of bromide (69). The yield was 86% intwo steps.

Synthesis of Nitrile Compound (70)

To 15 mL of water was dissolved 1.76 g (F.W. 49.01, 36.0 mmol) of sodiumcyanide and then, 20 mL of ethanol was added thereto. To the resultingsolution was slowly added 10.2 g (F.W. 339.25, 30.0 mmol) of bromide(69) at room temperature. This mixed solution was heated to 80° C. andstirred at the same temperature for 30 minutes. This reaction solutionwas cooled by standing to room temperature while vigorously stirring.Ethanol was removed under reduced pressure and water was added to theremaining solution. The deposited crude crystals were collected byfiltration and washed with water. After drying, 8.13 g of a crudenitrile compound was obtained. These crude crystals were recrystallizedfrom ethyl acetate-hexane to obtain 7.30 g (yield 85.3%) of nitrilecompound (70).

Synthesis of Ethylated Compound (71)

To a solution of 22.8 g (F.W. 285.37, 80.0 mmol) of nitrile compound(70) in 50 mL of methylene chloride was added dropwise 6.72 mL (F.W.155.95, d=1.94, 84.0 mmol) of ethyl iodide and stirred. Furthermore,27,2 g (F.W. 339.54, 80.0 mmol) of tetrabutylammonium hydrogen sulfatewas added thereto to completely dissolve nitrile compound (70). To thissolution was added dropwise a 20% sodium hydroxide aqueous solution (80g) and then, stirred at room temperature for one hour. Under coolingwith ice, the reaction was neutralized by addition of 4N hydrochloricacid and then, extracted with methylene chloride and the organic layerwas washed with water and a saturated sodium chloride aqueous solution.The obtained solution was dried with anhydrous magnesium sulfate andthen, the solvent was removed under reduced pressure to obtain an oilyproduct. To the residue was added a 3:1=hexane:ethyl acetate mixture toremove tetrabutylammonium iodide deposited by filtration. The filtratewas removed under reduced pressure to obtain 27.0 g of crude ethylatedcompound (71).

Synthesis of Phenylacetic Acid (72)

To a mixture of 27.0 g (F.W. 313.41, 77.2 mmol) of crude ethylatedcompound (71) and 66 mL of ethylene glycol was added a 30% sodiumhydroxide aqueous solution (42.7 g). The resulting solution was stirredat 150° C. overnight. To the reaction solution was added ice and theresulting solution was neutralized with 4N hydrochloric acid. Theneutralized solution was extracted with ethyl acetate and the extractwas washed with water and then with a saturated sodium chloride aqueoussolution. The obtained solution was dried with anhydrous magnesiumsulfate and then, the solvent was completely removed under reducedpressure to obtain 29.0 g of crude phenylacetic acid (72). This crudephenyacetic acid was recrystallized from ethyl acetate-hexane to, obtain23.0 g of phenylacetic acid (72). The yield was 87% in two steps.

Synthesis of Cyclized Compound (51)

To 10.0 g (F.W. 332.41, 30.1 mmol) of dried phenylacetic acid (72) wasadded 50 mL of methanesulfonic acid to dissolve phenylacetic acid (72)and then, stirred at room temperature overnight. To the reactionsolution was added water under cooling with ice and then, the resultingsolution was partitioned with ethyl acetate and water, and the organiclayer was washed with water and then with a saturated sodium chlorideaqueous solution. The obtained solution was dried with anhydrous sodiumsulfate and then, the solvent was removed under reduced pressure toobtain 9.52 g of a crude product. A small amount of ethyl acetate wasadded to this crude product which was then collected by filtration then,the residue was washed with a small amount of ethyl acetate to obtain8.84 g (yield 93.4%) of cyclized compound (52).

To 25.0 g (F.W. 314.40, 80.0 mmol) of cyclized compound (51) was added150 g of pyridine hydrochloride and stirred at 200° C. for two hours. Tothe reaction mixture was added diluted hydrochloric acid and ethylacetate and the resulting solution was extracted, and the organic layerwas washed with water and then with a saturated sodium chloride aqueoussolution and dried with anhydrous magnesium sulfate. The concentratedresidue was dissolved in 800 mL of ethyl acetate and polar substanceswere adsorbed on 50 g silica gel and 25 g of Florisil and then,filtered. Ethyl acetate in the filtrate was concentrated and then, theresidue was recrystallized from ethyl acetate-hexane to obtain 19.9 g(yield 87%) of the title compound.

Example 165

Preparation of11-Ethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 4)

Synthesis of Ethylated Compound (74)

To a solution of 30.0 g (F.W. 196.05, 153 mmol) of nitrile compound (73)and 13.6 mL (F.W. 155.97, d=1.94, 169 mmol) of ethyl iodide in 50 mL oftoluene was quickly added a suspension of 51.8 g (F.W. 339.54, 153 mmol)of tetrabutylammonium hydrogen sulfate and a 20% sodium hydroxideaqueous solution (300 g) on an ice bath and stirred at room temperaturefor two hours. The crystals of tetrabutylammonium iodide produced wereseparated by filtration and the crystals were washed with 200 mL oftoluene. The organic layer was washed with water and then with asaturated sodium chloride aqueous solution and dried with anhydrousmagnesium sulfate. The solvent was removed under reduced pressure toobtain 34.4 g of ethylated compound (74).

Synthesis of Carboxylic Acid (75)

To 34.4 g (F.W. 224.10) of ethylated compound (74) were added a 6Nsodium hydroxide aqueous solution (75.0 mL) and 75.0 mL of ethanol andstirred at 100° C. for two days. Ethanol was removed under reducedpressure and then, to the resulting solution was added toluene to effectpartition. To the aqueous layer was added concentrated hydrochloric acidand the resulting solution was made pH 3. The solution thus obtained wasextracted with ethyl acetate and washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure toobtain about 38 g of a crude product. This crude product wasrecrystallized from hexane to obtain 33.5 g of carboxylic acid (75). Theyield was 90% in two steps.

Synthesis of Phenylacetic Acid (72)

A mixture of 26.7 g (F.W. 243.10, 110 mmol) of carboxylic acid (75),18.7 g (F.W. 170.23, 110 mmol) of 3,4-dimethoxythiophenol (76), 3.50 g(F.W. 63.55, 55.0 mmol) of copper (powder), 10.5 g (F.W. 190.45, 55.0mmol) of copper (I) iodide, 18.2 g (F.W. 138.21, 132 mmol) of potassiumcarbonate and 140 mL of N-methyl-2-pyrrolidone was stirred at 140° C.for 3.5 hours. To the reaction solution was added ice and the resultingsolution was made pH 6 to 7 with concentrated hydrochloric acid undercooling with ice. Toluene and water were added thereto to dissolve theproduct, and insolubles were separated by filtration. To the filtratewas added a 20% sodium hydroxide aqueous solution to effect partition.The organic layer was separated and further extracted with a 2% sodiumhydroxide aqueous solution and then, combined with the aqueous layer andmade pH 2 to 3 with concentrated hydrochloric acid under cooling withice. The obtained solution was extracted with ethyl acetate and theorganic layer was washed with water, and dried with anhydrous sodiumsulfate and then, the solvent was removed under reduced pressure toobtain 35.1 g of a crude product. This product was washed with a smallamount of diisopropyl ether and then, dried to obtain 28.7 g (yield78.6%) of phenylacetic acid (72).

Synthesis of Cyclized Compound (51)

To 28.6 g (F.W. 332.41, 86.0 mmol) of dried phenylacetic acid compound(72) was added 140 mL of methanesulfonic acid and stirred at roomtemperature overnight. The reaction solution was added dropwise to icewater and the deposit was collected by filtration and then, washed withwater. After drying, 26.9 g (yield 99.4%) of cyclized compound (51) wasobtained.

To 18.9 g (F.W. 314.40, 60.0 mmol) of cyclized compound (51) was added56.6 g of pyridine hydrochloride and stirred at 185° C. for six hours.The reaction mixture was completely cooled to room temperature and then,ice water and ethyl acetate were added thereto and the resultingsolution was extracted therewith. The organic layer was washed withwater and a saturated sodium chloride aqueous solution, subsequentlydried with anhydrous sodium sulfate, and the solvent was removed underreduced pressure to obtain 16.2 g of a crude product. This crude productwas recrystallized from 60% isopropyl alcohol to obtain 15.9 g (yield92.4%) of the title compound.

Example 166

Preparation of(+)-11-Ethyl-7,9-dihydroxy-10,11-dihydrobenzo[b,f]thiepin-10-one[Optical Isomer (+) of Compound of Example 4]

Compound of Example 4 was subjected to optical resolution by a columnunder the conditions as described below to obtain a frontal peak. Thiscompound had a specific rotation [α]_(D) (20° C.) of +16.7.

Column: CHIRALPAK AD

Mobile Phase: n-hexane/ethanol/acetic acid=40/60/0.1 (vol/vol)

Example 167

Preparation of(−)-11-Ethyl-7,9-dihydroxy-10,11-dihydrobenzo[b,f]thiepin-10-one[Optical Isomer (−) of Compound of Example 4]

Compound of Example 4 was subjected to optical resolution by a columnunder the conditions as described below to obtain a rear peak. Thiscompound had a specific rotation [α]_(D) (20° C.) of −16.7.

Column: CHIRALPAK AD

Mobile Phase: n-hexane/ethanol/acetic acid=40/60/0.1 (vol/vol)

Example 178

Preparation of α-Ethyl-2-bromophenylacetic Acid (75)

It was confirmed that the title compound obtained by the same method asdescribed in Example 165 of up to the second step had the followingproperties.

Description: Colorless plate crystals.

Melting Point: 37-39° C. (cold hexane) ¹H NMR (400 MHz, CDCl₃) δ: 0.94(3H, dd, J=7.4, 7.4 Hz), 1.83 (1H, ddq, J=14.9, 7.4, 7.4 Hz), 2.10 (1H,ddq, J=14.9, 7.4, 7.4 Hz), 4.14 (1H, dd, J=7.4, 7.4 Hz), 7.12 (1H, ddd,J=8.0. 7.5, 1.6 Hz), 7.29 (1H, ddd, J=7.8, 7.5, 1.2 Hz), 6.94 (1H, dd,J=7.8, 1.2 Hz), 7.38 (1H, dd, J=8.0, 1.6 Hz) EIMS m/z: 244, 242 (M+),199, 197, 171, 169, 163 IR (KBr)cm⁻¹: 1705 UV λ_(max) (EtOH) nm (ε): 274(40), 264 (300).

Example 179

Preparation of α-Ethyl-2-[(3,4-dimethoxyphenyl)thio]phenylacetic Acid(72)

It was confirmed that the title compound obtained by the same method asdescribed in Example 164 of up to the sixth step and in Example 165 ofup to the third step had the following properties.

Description: Light brown amorphous powder.

Melting Point: 115.2-117.0° C. (Dec.) ¹H NMR (400 MHz, CDCl₃) δ: 0.92(3H, dd, J=7.4, 7.4 Hz), 1.79 (1H, ddq, J=14.8, 7.4, 7.4 Hz), 2.12 (1H,ddq, J=14.8, 7.4, 7.4 Hz), 3.79 (3H, s), 3.87 (3H, s), 4.33 (1H, dd,J=7.4, 7.4 Hz), 6.80 (1H, d, J=8.3 Hz), 6.88 (1H, d, J=1.9 Hz), 6.94(1H, dd, J=8.3, 1.9 Hz), 7.14-7.26 (3H, m), 7.37 (1H, d, J=1.8, Hz) EIMSm/z: 332 (M⁺, Base) IR (KBr) cm⁻¹: 1705, 1585, 1504, 1442 UV λ_(max)(EtOH) nm (ε): 250 (15200), 283 (8000).

Example 180

To a mixture of 1.00 g (F.W. 286.37, 3.50 mmol) of the compound ofExample 4 and 1N NaOH (4 mL) was added 6 mL of acetone dissolving 1.40 g(F.W. 397.2, 3.50 mmol) of methyl acetobromoglucuronate in smallportions at 0° C. and stirred at room temperature for six hours whileadjusting the pH to around 6 with 1N NaOH. After concentration, 20% NaOH(11.2 mL) was added to the concentrated solution and stirred at roomtemperature for 30 minutes. After cooling, to the obtained solution wasadded 5 mL of concentrated hydrochloric acid attentively and theresulting solution was made pH 2 to 3 with 1N hydrochloric acid anddesalted with a column packed with “HP-20”. The column was thoroughlywashed with water, and then, the desired fraction was eluted with 100%methanol. The starting material was removed from 2.57 g of the obtainedcrude product by silica gel chromatography (silica gel 8 g; eluent; 33%ethyl acetate:hexane→20% ethanol:ethyl acetate). After concentration,the obtained crude product was further purified by HPLC (detection; 280nm; mobile phase, 50% MeCN—H₂O containing 0.2% of AcOH). Theconcentrated oily substance was dissolved in dioxane and freeze-dried toobtain 463 mg (yield 36%) of the title compound.

TEST EXAMPLES

It will now be shown that the compounds of the present invention haveexcellent pharmacological activities with reference to Test Examples.

Test Example 1

Dilating Action on Contraction of Tracheal Smooth Muscles

With the use of pig tracheal muscles, the action of the compounds of thepresent invention on contraction of tracheal muscles has beeninvestigated. The method refers to “Smooth Muscle Manual” (published byBun'eido Publishing Co.), pp. 125-137. The trachea cartilage mucousmembrane and submucous tissue of a pig trachea were removed to prepare aspecimen of tracheal smooth muscles having a major diameter of about 10mm and a minor diameter of about 1.5 mm. This specimen was suspended ina Magnus tube which was aerated with a mixed gas of 95% of oxygen and 5%of carbon dioxide and contained nutrient solution at 37° C. and a loadof 0.8 g was applied to this specimen, and after the tension of thespecimen was stabilized, the nutrient solution was replaced with a highconcentration K⁺ solution (72.7 mM) to provoke K⁺ contraction. Theprocedure of replacing the solution in the Magnus tube with the nutrientsolution to wash the solution and provoking K⁺ contraction with the highconcentration K⁺ solution was repeated again until the contraction forcebecame constant. When the tension of the K⁺ contraction became constant,each of the compounds described in Table 19 (the structural formula ofthe Comparative Example being described in the right side of thecompound of the above described Example 180) was added to the highconcentration K⁺ solution as the test substance to measure the change intension. The test substance was dissolved in dimethyl sulfoxide at apredetermined concentration and added to the high concentration K⁺solution in such a manner that the final concentration came to 10 μM.With the use of pig tracheal muscles, the action of the compounds of thepresent invention on contraction of tracheal muscles has beeninvestigated. The method refers to “Smooth Muscle Manual” (published byBun'eido Publishing Co.), pp. 125-137. The trachea cartilage mucousmembrane and submucous tissue of a pig trachea were removed to prepare aspecimen of tracheal smooth muscles having a major diameter of about 10mm and a minor diameter of about 1.5 mm. This specimen was suspended ina Magnus tube which was aerated with a mixed gas of 95% of oxygen and 5%of carbon dioxide and contained nutrient solution at 37° C. and a loadof 0.8 g was applied to this specimen, and after the tension of thespecimen was stabilized, the nutrient solution was replaced with a highconcentration K+ solution (72.7 mM) to provoke K+ contraction. Theprocedure of replacing the solution in the Magnus tube with the nutrientsolution to wash the solution and provoking K+ contraction with the highconcentration K+ solution was repeated again until the contraction forcebecame constant. When the tension of the K+ contraction became constant,each of the compounds described in Table 19 (the structural formula ofthe Comparative Example being described in the right side of thecompound of the above described Example 180) was added to the highconcentration K+ solution as the test substance to measure the change intension. The test substance was dissolved in dimethyl sulfoxide at apredetermined concentration and added to the high concentration K+solution in such a manner that the final concentration came to 10 mM.Further, the final concentration of dimethyl sulfoxide added was made0.3% or less. The change in tension was led to a strain pressureamplifier (“AP-621G3”, manufactured by Nippon Koden Kogyo) through a FDpickup transducer (“TB-611T”, manufactured by Nippon Koden Kogyo) andrecorded on a recorder (“R-64V”, manufactured by Rika Electric). Whenthe tension before replacement with the high concentration K+ solutionwas regarded as 0% and the last tension which was generated by the highconcentration K+ solution before the addition of a test substance wasregarded as 100%, the contraction force of the tracheal smooth muscletwo hours after addition of a test substance was shown as relativepercentage. Further in this instance, the contraction by the highconcentration K+ solution was approximately constant for at least twohours after the tension had been stabilized. The results are shown inTable 19.

TABLE 19 Relative Contraction Example No. Force (%) 1 0 4 2.7 17 0 271.4 37 7.5 82 22.4 110 10.9 124 30.3 Comparative 54.5 Example

Test Example 2

Inhibition of Immediate Asthmatic Response, Late Asthmatic Response andInfiltration of Inflammatory Cells into Lung of Guinea Pigs

It is reported [Pepys, J. and Hutchcroft, B. J., Bronchial provocationtests in etiologic diagnosis and Analysis of asthma, Am. Rev. Respir.Dis., 112, 829-859 (1975)] that when asthmatic patients are allowed toinhale an antigen, immediate asthmatic response (hereinafter referred toas “IAR”) whose peak is 15 to 30 minutes after inhalation is provokedand recovery from this response is within two hours; however, in 60% ofthe asthmatic patients late asthmatic response (hereinafter referred toas “LAR”) appears 4 to 12 hours after the inhalation of the antigen. LARis considerably prolonged and is similar to a natural attack of asthma,particularly an attack of intractable asthma and thus, it is thoughtvery important for the therapy of bronchial asthma to clarify thepathology. On the other hand, it is known that when the guinea pigsactively sensitized with an antigen are allowed to inhale the antigenagain, biphasic airway responses are caused. Accordingly, as the animalmodel line of IAR and LAR which are recognized in the above describedasthmatic patients, the asthmatic model using guinea pigs is widely usedin the evaluation of drugs for asthma and the like. Furthermore, it isknown that in the IAR and LAR model of guinea pigs, when activelysensitized guinea pigs are exposed to an antigen, infiltration ofinflammatory cells into the airway occurs together with the biphasicairway contraction to cause various inflammatory disorders to airwaytissues thereby. Therefore, the number of inflammatory cells in thebronchoalveolar lavage fluid is widely used as the index for theinfiltration of inflammatory cells into the airway. Each of the abovedescribed actions in the IAR and LAR model of guinea pigs was examinedwith the compounds of the present invention.

Experimental Method

(1) Sensitization

Guinea pigs were allowed to inhale a 1% ovalbumin (“OVA”, sigma-AldrichCo., U.S.A.) physiological saline for 10 minutes daily continuously for8 days using of an ultrasonic nebulizer (“NE-U12”, Omron, Japan).

(2) Challenge

One week after the final sensitization, the guinea pigs were allowed toinhale a 2% “OVA” physiological saline for 5 minutes using of thenebulizer. Twenty-four hours and one hour before challenge, the guineapigs were dosed with metyrapone (10 mg/kg, Sigma-Aldrich Co., U.S.A.)intravenously, and dosed with pyrilamine (10 mg/kg, Sigma-Aldrich Co.,U.S.A.) intraperitoneally 30 minutes before challenge.

(3) Preparation of Test Substance and Method of Administration

Each of the test substances (Compounds of Examples 1 and 4) was formedinto a suspension with a 0.5% carboxymethyl cellulose sodium salt(hereinafter referred to as “CMC-Na”) solution at a concentration of 2mg/mL. One hour before challenge, the guinea pigs were orally dosed withthe suspension of the test substance with such a dose so as to be 10mg/kg. For the control group the medium (a 0.5% CMC-Na solution) wasused.

(4) Measurement of Airway Resistance

The specific airway resistance (hereinafter referred to as “sRaw”) wasmeasured, 1 minute, 10 minutes and 30 minutes after challenge andfurthermore, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7hours, 8 hours and 24 hours, each time for the duration of 1 minute withthe use of airway resistance measuring equipment (“Pulmos-1”, M.I.P.S.,Japan).

(5) Measurement of Number of Inflammatory Cells in Broncho-AlveolarLavage Fluid

Twenty-three to twenty-four hours after the antigen challenge, theabdominal aorta of the guinea pigs was cut under intraperitonealanesthesia with “Nembutal” (50 mg/kg) to remove blood and the chest wasopened. A tube was inserted in the bronchus and fixed thereto andthrough this tube, 5 mL (37° C.) of a physiological saline was injectedand sucked therethrough; this procedure was repeated twice (10 mL intotal) and the recovered fluid was regarded as the bronchoalveolarlavage fluid (hereinafter referred to as “BALF”). BALF was centrifugedat 1,100 rmp at 4° C. for 10 minutes to obtain a precipitate (a pellet).This pellet was suspended in 1 mL of a physiological saline and aTurkliquid was added thereto and the number of leukocytes per μL wascounted with a leukocyte counter plate. Centrifugation was repeatedunder the above described conditions and rabbit serum was added to theobtained pellet to prepare a smear preparation. After drying, thepreparation was subjected to the May Grunwald-Giemsa stain. The numberof leukocytes was counted by a microscope and the ratio to the totalnumber of cells of neutrophils, eosinophils, macrophages and lymphocyteswas obtained and the number of cells per μL was calculated on the basisof this ratio.

(6) Statistical Analysis

The obtained test results were shown by mean values and standarddeviations and the student's t-test was carried out. The level ofsignificance was set to 5% or less. The number of animals used in eachtest group was 6.

Results

(1) Antigen Induced Immediate and Late Asthmatic Responses

As shown in FIG. 1, with the actively sensitized guinea pigs, the airwayresistance quickly increased by inhalation of “OVA” and increased afterone minute, on average, by 475% of that before the challenge.Thereafter, the airway resistance quickly was reduced and decreased to52% after three hours. Furthermore, the airway resistance increasedagain and reached 156% after 6 hours. The area under the response curve(hereinafter referred to as “AUC”) from 4 hours to 8 hours was 466%·hr.From this, the biphasic response of the immediate asthmatic responsewhich occurred within 30 minutes after the challenge (IAR) by the “OVA”inhalation and the late asthmatic response which occurred several hours(LAR) after the challenge was recognized.

Here, when Compounds of Examples 1 and 4 were orally dosed with 10 mg/kgone hour before the “OVA” challenge, each IAR (% change in sRaw) wasinhibited by 70% and 73%, and LAR (AUC) was inhibited by 77% and 86%compared to the control group (FIG. 2).

(2) Number of Cells in Bronchoalveolar Lavage Fluid

The results are shown in FIG. 3. In the actively sensitized guinea pigsby the “OVA” inhalation, the total number of cells in thebronchoalveolar lavage fluid 24 hours after the antigen challenge was,on average, 6,667/μL, and the numbers of cells of macrophages,neutrophils, eosinophils and lymphocytes were, on average, 2,499, 2,487,1,622 and 59/μL, respectively.

When Compound of Example 1 was orally dosed with 10 mg/kg one hourbefore the “OVA” challenge, the total number of cells was, on average,3,775/μL, and the numbers of cells of macrophages, neutrophils,eosinophils and lymphocytes were, on average, 1,872, 1,072, 810 and21/μL, respectively; a significant decrease in the total number of cellsand a tendency for the numbers of cells of neutrophils, eosinophils andlymphocytes to decrease compared to the control group were recognized.On the other hand, when Compound of Example 4 was orally dosed with 10mg/kg one hour before the “OVA” challenge, the total number of cellswas, on average, 4,304/μL, and the numbers of cells of macrophages,neutrophils, eosinophils and lymphocytes were, on average, 2,478, 1,062,700 and 64/μL, respectively; a significant decrease in the total numberof cells and eosinophils and a tendency for the numbers of cells ofneutrophils to decrease compared to the control group were recognized.

From the above results, both Compounds of Examples 1 and 4 exhibitedinhibition against the immediate and late asthmatic responses of guineapigs and, in addition, inhibition against the increase in the number ofinflammatory cells in the bronchoalveolar lavage fluid and suggested apossibility that they would become promising drugs for the therapy ofasthma in clinical trials.

Test Example 3

Action on Antigen Induced Airway Hypersensitivity in Actively SensitizedGuinea Pigs

Bronchial asthma is a disease characterized by bronchial contraction,airway hypersensitivity and infiltration of inflammatory cells into theairway. Airway hypersensitivity is a condition in which the airwaysensitively produces a contraction response to various slight stimuli.Particularly, airway hypersensitivity is considered to be a commonfeature among patients suffering from allergic bronchial asthma. Thisexperimental system in which actively sensitized guinea pigs are used isuseful as a airway hypersensitivity model.

(1) Sensitization

Guinea pigs were allowed to inhale a 1% “OVA” (Sigma Aldrich Co., U.S.A)physiological saline for 10 minutes daily continuously for 8 days withthe use of an ultrasonic nebulizer (“NE-U12”, Omron, Japan).

(2) Challenge

One week after the final sensitization, the guinea pigs were allowed toinhale a 2% “OVA” physiological saline for 5 minutes. Twenty-four hoursbefore challenge and one hour before challenge, the guinea pigs weredosed with metyrapone (10 mg/kg, Sigma-Aldrich Co., U.S.A.)intravenously, and dosed with pyrilamine (10 mg/kg, Sigma-Aldrich Co.,U.S.A.) intraperitoneally 30 minutes before challenge.

(3) Preparation of Test Substance and Method of Administration

Test substance (Compound of Example 4) was formed into a suspension witha 0.5% CMC-Na solution at each predetermined concentration. In twogroups of guinea pigs, one hour before challenge, the guinea pigs of theeach group were orally dosed with the suspension of the test substancewith a dose set at 10 mg/kg or 30 mg/kg respectively and in other onegroup, the guinea pigs were orally dosed with the test substance twice,16 hours before challenge and 2 hours before challenge, with a dose setat 30 mg/kg. Dexamethasone was formed into a suspension with a 0.5%CMC-Na solution which was then dosed twice, 16 hours before theantigen-challenge and 2 hours before the antigen-challenge, with a doseset at 10 mg/kg. For the control group the medium (a 0.5% CMC-Nasolution) was used. The doses were all set at 5 mL/kg.

(4) Measurement of Airway Resistance

The specific airway resistance (sRaw) of wake guinea pigs was measuredby the double flow plethysmography with the use of airway resistancemeasuring equipment (“Pulmos-1”, M.I.P.S., Japan).

(5) Measurement of Airway Reactivity

For two hours, from twenty-two to twenty-six hours after the antigenchallenge, the guinea pigs were placed in an animal chamber and allowedto inhale a physiological saline and acetylcholine (hereinafter referredto as “ACh”) solutions of 0.0625, 0.125, 0.25, 0.5, 1 and 2 mg/mL ,respectively, in the order named, each for one minute until sRaw came tothe value at least twice the baseline sRaw (sRaw after the inhalation ofthe physiological saline). The ACh concentration (hereinafter referredto as “PC₁₀₀ACh”) necessary for 100% increase in the baseline sRaw wascalculated from the concentration of ACh and sRaw-resistance curve.

(6) Statistical Analysis

The obtained test results were shown by mean values and standarddeviations and the student's t-test was carried out. The level ofsignificance was set to 5% or less. The number of animals used in eachtest group was 6.

Results

The results are shown in FIG. 4. In the guinea pigs actively sensitizedby the “OVA” inhalation, the airway reactivity to ACh 22 hours to 26hours after the challenge of antigen-antibody reaction was measured. ThePC₁₀₀ACh of the control group using the medium alone was 0.15 mg/mL.According to the report [Fuchikami, J-I, et al, Pharmacological study onantigen induced immediate and late asthmatic responses in activelysensitized guinea-pigs, Jap, J. Pharmacol., 71, p196 (1996)] on the samesystem, the PC₁₀₀ACh of guinea pigs challenged by a physiological salinein the guinea pigs actively sensitized by the “OVA” inhalation was, onaverage, 1.20 mg/mL and thus, in the control group of the presentexperiment the antigen induced airway hypersensitivity was clearlyrecognized. Further, when dexamethasone used as the positive control wasorally dosed with 10 mg/kg 16 hours and 2 hours before the “OVA”challenge, the PC100ACh was 1.14 mg/mL, the airway hypersensitivity wassignificantly inhibited compared to the control group. On the otherhand, when Compound of Example 4 was orally dosed with 10 and 30 mg/mL,respectively, one hour before the “OVA” challenge, the PC₁₀₀ACh was 0.59and 1.63 mg/mL, respectively, and exhibited a dose-dependent inhibition.Further, when Compound of Example 4 was orally dosed with 30 mg/kg twice16 hours and 2 hours before the “OVA” challenge, the PC₁₀₀ACh was 1.24mg/mL, and the airway hypersensitivity was significantly inhibitedcompared to the control group.

From the above results, it is clear that Compound of Example 4 has astrong inhibition against the hypersensitivity in sensitized guinea pigsand, and it has suggested a possibility that Compound of Example 4 wouldbecome a promising anti-asthmatic drug even in clinical trials.

Test Example 4

Toxicity Study of Two-Week Repeated-Dose Oral Administration with Rats

In order to study the toxicity by repeated-dose administration ofcompounds, the compounds were dosed orally to Sprague-Dawley line rats(three male rats per group) with 0, 125 and 500 mg/kg/day (a 0.5 w/v %CMC-Na solution) repeatedly for two weeks. The results are shown inTable 20.

TABLE 20 Example No. Results Comparative Kidney damage were observedwith Example 125 mg/kg or more. Example 1 No abnormalities wererecognized in any dosed group. Example 4 Tendency to weight inhibitionwas recognized in the group with 500 mg/kg.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have a wide range ofpharmacological actions such as an excellent tracheal smooth musclerelaxing action, an inhibition of airway hypersensitivity and aninhibition of infiltration of inflammatory cells into the airway andalso high safety and accordingly, are very promising as drugs.

What is claimed is:
 1. A compound of the following formula,

wherein Q is a lower alkyl group,an optical isomer thereof or a saltthereof.
 2. A compound of the following formula,

wherein Q is a lower alkyl group; and Q₁ to Q₅, which may be the same ordifferent, are each independently any one selected from a hydrogen atom,a lower alkoxy group and a hydroxyl group, an optical isomer thereof ora salt thereof.
 3. The compound of claim 1 wherein Q is a methyl group.4. The compound of claim 1 wherein Q is an ethyl group.
 5. The compoundof claim 1 wherein Q is an n-propyl group.
 6. The compound of claim 1wherein Q is an n-butyl group.
 7. The compound of claim 2 wherein atleast two of Q₁ to Q₅ are hydroxyl groups.
 8. The compound of claim 2wherein at least two of Q₁ to Q₅ are lower alkoxy groups.
 9. Thecompound of claim 2 wherein at least two of Q₁ to Q₅ are hydroxyl orlower alkoxy groups.
 10. The compound of claim 2 wherein two of Q₁ to Q₅are hydroxyl or lower alkoxy groups.
 11. The compound of claim 2 whereinQ is a methyl group, and ethyl group, an n-propyl group, or an n-butylgroup.
 12. The compound of claim 11 wherein at least two of Q₁ to Q₅ arehydroxyl groups.
 13. The compound of claim 11 wherein at least two of Q₁to Q₅ are lower alkoxy groups.
 14. The compound of claim 11 wherein atleast two of Q₁ to Q₅ are hydroxyl or lower alkoxy groups.
 15. Thecompound of claim 11 wherein two of Q₁ to Q₅ are hydroxyl or loweralkoxy groups.